4-15540994-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3BP4_StrongBP6BS1BS2

The NM_001378615.1(CC2D2A):c.2161C>T(p.Pro721Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,549,670 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 8 hom. )

Consequence

CC2D2A
NM_001378615.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 7.64

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.033253044).

BP6

Variant 4-15540994-C-T is Benign according to our data. Variant chr4-15540994-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194821.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=4, Uncertain_significance=1}. Variant chr4-15540994-C-T is described in Lovd as [Pathogenic]. Variant chr4-15540994-C-T is described in Lovd as [Benign]. Variant chr4-15540994-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00111 (169/152216) while in subpopulation SAS AF= 0.0127 (61/4814). AF 95% confidence interval is 0.0101. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CC2D2A	NM_001378615.1 link	c.2161C>T	p.Pro721Ser	missense_variant	Exon 17 of 37	ENST00000424120.6	NP_001365544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CC2D2A	ENST00000424120.6 link	c.2161C>T	p.Pro721Ser	missense_variant	Exon 17 of 37	5	NM_001378615.1	ENSP00000403465.1		Q9P2K1-4

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

169

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000852

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0127

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000867

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00240

AC:

374

AN:

155590

Hom.:

AF XY:

0.00281

AC XY:

231

AN XY:

82106

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000657

Gnomad ASJ exome

AF:

0.00694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0000599

Gnomad NFE exome

AF:

0.000959

Gnomad OTH exome

AF:

0.00322

GnomAD4 exome

AF:

0.00165

AC:

2308

AN:

1397454

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1319

AN XY:

689170

show subpopulations

Gnomad4 AFR exome

AF:

0.000317

Gnomad4 AMR exome

AF:

0.000506

Gnomad4 ASJ exome

AF:

0.00796

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00991

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.00105

Gnomad4 OTH exome

AF:

0.00221

GnomAD4 genome

AF:

0.00111

AC:

169

AN:

152216

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0127

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000867

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000801

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000505

AC:

ExAC

AF:

0.00169

AC:

142

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CC2D2A: PM5, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 08, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1, PP3 -

not specified

Benign:2

Mar 16, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 08, 2017

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Joubert syndrome 1

Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Meckel syndrome, type 6

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.90

D;.

MetaRNN

Benign

0.033

T;T

MetaSVM

Pathogenic

0.80

MutationAssessor

Uncertain

2.7

M;M

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.1

D;D

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MVP

0.97

MPC

0.30

ClinPred

0.067

GERP RS

4.9

Varity_R

0.80

gMVP

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over