4-15567523-A-C

Variant names:

• chr4-15567523-A-C
• rs13116304
• NM_001378615.1:c.3288+41A>C

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.3288+41A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 1,544,902 control chromosomes in the GnomAD database, including 389,668 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (36503 hom., cov: 31)
  • Exomes 𝑓: 0.71 (353165 hom.)
• Consequence: CC2D2A NM_001378615.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.28
• Publications: 16 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

LOC124900671 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 4-15567523-A-C is Benign according to our data. Variant chr4-15567523-A-C is described in ClinVar as Benign. ClinVar VariationId is 126239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.746 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1	c.3288+41A>C		intron_variant	Intron 25 of 36	ENST00000424120.6	NP_001365544.1
CC2D2A	NM_001080522.2	c.3288+41A>C		intron_variant	Intron 26 of 37		NP_001073991.2
CC2D2A	NM_001378617.1	c.3141+41A>C		intron_variant	Intron 23 of 34		NP_001365546.1
LOC124900671	XR_007058061.1	n.130+3208T>G		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6	c.3288+41A>C		intron_variant	Intron 25 of 36	5	NM_001378615.1	ENSP00000403465.1

Frequencies

GnomAD3 genomes AF: 0.691 AC: 104982 AN: 151842 Hom.: 36476 Cov.: 31

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.758

Gnomad ASJ AF: 0.737

Gnomad EAS AF: 0.540

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.679

Gnomad MID AF: 0.699

Gnomad NFE AF: 0.720

Gnomad OTH AF: 0.687

GnomAD2 exomes AF: 0.710 AC: 158675 AN: 223330 AF XY: 0.709

Gnomad AFR exome AF: 0.637

Gnomad AMR exome AF: 0.795

Gnomad ASJ exome AF: 0.723

Gnomad EAS exome AF: 0.533

Gnomad FIN exome AF: 0.687

Gnomad NFE exome AF: 0.725

Gnomad OTH exome AF: 0.727

GnomAD4 exome AF: 0.711 AC: 990404 AN: 1392940 Hom.: 353165 Cov.: 21 AF XY: 0.712 AC XY: 494788 AN XY: 695256

African (AFR) AF: 0.632 AC: 19530 AN: 30910

American (AMR) AF: 0.790 AC: 29258 AN: 37044

Ashkenazi Jewish (ASJ) AF: 0.724 AC: 18084 AN: 24972

East Asian (EAS) AF: 0.562 AC: 21990 AN: 39094

South Asian (SAS) AF: 0.715 AC: 57257 AN: 80058

European-Finnish (FIN) AF: 0.684 AC: 36336 AN: 53130

Middle Eastern (MID) AF: 0.715 AC: 4019 AN: 5618

European-Non Finnish (NFE) AF: 0.717 AC: 763420 AN: 1064108

Other (OTH) AF: 0.698 AC: 40510 AN: 58006

GnomAD4 genome AF: 0.691 AC: 105050 AN: 151962 Hom.: 36503 Cov.: 31 AF XY: 0.690 AC XY: 51236 AN XY: 74304

African (AFR) AF: 0.632 AC: 26170 AN: 41408

American (AMR) AF: 0.758 AC: 11575 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.737 AC: 2553 AN: 3466

East Asian (EAS) AF: 0.540 AC: 2783 AN: 5152

South Asian (SAS) AF: 0.706 AC: 3397 AN: 4814

European-Finnish (FIN) AF: 0.679 AC: 7177 AN: 10566

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.720 AC: 48970 AN: 67976

Other (OTH) AF: 0.681 AC: 1435 AN: 2106

Alfa AF: 0.709 Hom.: 149009

Bravo AF: 0.696

Asia WGS AF: 0.643 AC: 2235 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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. -

not provided Benign:2

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Meckel syndrome, type 6 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 9 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.014
DANN	Benign	0.62
PhyloP100		-2.3
Mutation Taster		=100/0	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: rs13116304; hg19: chr4-15569146; COSMIC: COSV67502712; COSMIC: COSV67502712;