rs16892095

Variant names:

• chr4-15516734-A-C
• rs16892095
• NM_001378615.1:c.1127A>C

Your query was ambiguous. Multiple possible variants found:

• chr4-15516734-A-C
• chr4-15516734-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378615.1(CC2D2A):​c.1127A>C​(p.Glu376Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0319 in 1,612,224 control chromosomes in the GnomAD database, including 4,104 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E376V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.047 (489 hom., cov: 32)
  • Exomes 𝑓: 0.030 (3615 hom.)
• Consequence: CC2D2A NM_001378615.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 2.45
• Publications: 25 publications found

Genes affected

CC2D2A (HGNC:29253): (coiled-coil and C2 domain containing 2A) This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

CC2D2A Gene-Disease associations (from GenCC):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 9

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P
• retinitis pigmentosa 93

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• COACH syndrome 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Joubert syndrome with oculorenal defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024175048).
• BP6: Variant 4-15516734-A-C is Benign according to our data. Variant chr4-15516734-A-C is described in ClinVar as Benign. ClinVar VariationId is 126227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.237 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378615.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	NM_001378615.1	MANE Select	c.1127A>C	p.Glu376Ala	missense	Exon 11 of 37	NP_001365544.1
	CC2D2A	NM_001080522.2		c.1127A>C	p.Glu376Ala	missense	Exon 12 of 38	NP_001073991.2
	CC2D2A	NM_001378617.1		c.980A>C	p.Glu327Ala	missense	Exon 9 of 35	NP_001365546.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CC2D2A	ENST00000424120.6	TSL:5 MANE Select	c.1127A>C	p.Glu376Ala	missense	Exon 11 of 37	ENSP00000403465.1
	CC2D2A	ENST00000503292.6	TSL:1	c.1127A>C	p.Glu376Ala	missense	Exon 12 of 38	ENSP00000421809.1
	CC2D2A	ENST00000513811.5	TSL:1	n.1307A>C		non_coding_transcript_exon	Exon 11 of 18

Frequencies

GnomAD3 genomes AF: 0.0471 AC: 7170 AN: 152114 Hom.: 492 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.0379

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00945

Gnomad OTH AF: 0.0502

GnomAD2 exomes AF: 0.0764 AC: 18884 AN: 247244 AF XY: 0.0690

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.257

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.245

Gnomad FIN exome AF: 0.0357

Gnomad NFE exome AF: 0.00958

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0303 AC: 44300 AN: 1459992 Hom.: 3615 Cov.: 31 AF XY: 0.0308 AC XY: 22369 AN XY: 726162

African (AFR) AF: 0.0392 AC: 1310 AN: 33454

American (AMR) AF: 0.246 AC: 10950 AN: 44470

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 674 AN: 26064

East Asian (EAS) AF: 0.265 AC: 10518 AN: 39644

South Asian (SAS) AF: 0.0868 AC: 7447 AN: 85840

European-Finnish (FIN) AF: 0.0327 AC: 1742 AN: 53344

Middle Eastern (MID) AF: 0.0343 AC: 198 AN: 5766

European-Non Finnish (NFE) AF: 0.00815 AC: 9059 AN: 1111096

Other (OTH) AF: 0.0398 AC: 2402 AN: 60314

GnomAD4 genome AF: 0.0471 AC: 7170 AN: 152232 Hom.: 489 Cov.: 32 AF XY: 0.0526 AC XY: 3916 AN XY: 74412

African (AFR) AF: 0.0396 AC: 1647 AN: 41552

American (AMR) AF: 0.162 AC: 2476 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.249 AC: 1283 AN: 5158

South Asian (SAS) AF: 0.0983 AC: 474 AN: 4824

European-Finnish (FIN) AF: 0.0379 AC: 402 AN: 10602

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.00947 AC: 644 AN: 68026

Other (OTH) AF: 0.0511 AC: 108 AN: 2114

Alfa AF: 0.0275 Hom.: 1308

Bravo AF: 0.0565

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.0403 AC: 153

ESP6500EA AF: 0.0102 AC: 84

ExAC AF: 0.0666 AC: 8050

Asia WGS AF: 0.159 AC: 552 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.

Dec 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2023

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30558011)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Meckel syndrome, type 6 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Meckel-Gruber syndrome;C0431399:Joubert syndrome Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome 9 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.8
DANN	Benign	0.17
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.4
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.069
Sift	Benign	0.60	T
Sift4G	Benign	1.0	T
Polyphen		0.015	B
Vest4		0.043
MPC		0.045
ClinPred		0.0026	T
GERP RS		1.5
Varity_R		0.045
gMVP		0.30
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs16892095; hg19: chr4-15518357; COSMIC: COSV67503768;