chr15-34752648-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020660.3(GJD2):​c.796G>T​(p.Val266Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GJD2
NM_020660.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.99
Variant links:
Genes affected
GJD2 (HGNC:19154): (gap junction protein delta 2) This gene encodes a member of the connexin protein family. Connexins are gap junction proteins which are arranged in groups of 6 around a central pore to form a connexon, a component of the gap junction intercellular channel. The channels formed by this protein allow cationic molecule exchange between human beta cells and may function in the regulation of insulin secretion. [provided by RefSeq, Oct 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24472207).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GJD2NM_020660.3 linkc.796G>T p.Val266Leu missense_variant Exon 2 of 2 ENST00000290374.5 NP_065711.1 Q9UKL4
GJD2XM_017022438.2 linkc.643G>T p.Val215Leu missense_variant Exon 2 of 2 XP_016877927.1 A0A654IE23

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GJD2ENST00000290374.5 linkc.796G>T p.Val266Leu missense_variant Exon 2 of 2 1 NM_020660.3 ENSP00000290374.4 Q9UKL4

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 09, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.796G>T (p.V266L) alteration is located in exon 2 (coding exon 2) of the GJD2 gene. This alteration results from a G to T substitution at nucleotide position 796, causing the valine (V) at amino acid position 266 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.082
BayesDel_addAF
Uncertain
0.088
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
20
DANN
Benign
0.85
DEOGEN2
Uncertain
0.44
T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.015
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Benign
0.81
T
M_CAP
Benign
0.046
D
MetaRNN
Benign
0.24
T
MetaSVM
Uncertain
-0.27
T
MutationAssessor
Benign
-1.2
N
PrimateAI
Pathogenic
0.90
D
PROVEAN
Benign
1.2
N
REVEL
Uncertain
0.35
Sift
Benign
1.0
T
Sift4G
Benign
1.0
T
Polyphen
0.0020
B
Vest4
0.26
MutPred
0.47
Loss of catalytic residue at V266 (P = 0.0029);
MVP
0.81
MPC
0.92
ClinPred
0.67
D
GERP RS
4.9
Varity_R
0.12
gMVP
0.85

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.

Other links and lift over

dbSNP: rs1891120021; hg19: chr15-35044849; API