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:10
• 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: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• 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

Sel.	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	Q9P2K1-4
	CC2D2A	NM_001080522.2		c.1127A>C	p.Glu376Ala	missense	Exon 12 of 38	NP_001073991.2	Q9P2K1-4
	CC2D2A	NM_001378617.1		c.980A>C	p.Glu327Ala	missense	Exon 9 of 35	NP_001365546.1	H0Y941

Ensembl Transcripts

Sel.	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	Q9P2K1-4
	CC2D2A	ENST00000503292.6	TSL:1	c.1127A>C	p.Glu376Ala	missense	Exon 12 of 38	ENSP00000421809.1	Q9P2K1-4
	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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Joubert syndrome 9 (1)
-	-	1	Meckel syndrome, type 6 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

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;