15-34753124-C-T

Position:

• chr15-34753124-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020660.3(GJD2):​c.320G>A​(p.Arg107His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJD2 NM_020660.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.85

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJD2	NM_020660.3	c.320G>A	p.Arg107His	missense_variant	2/2	ENST00000290374.5	NP_065711.1
GJD2	XM_017022438.2	c.167G>A	p.Arg56His	missense_variant	2/2		XP_016877927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJD2	ENST00000290374.5	c.320G>A	p.Arg107His	missense_variant	2/2	1	NM_020660.3	ENSP00000290374.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461870 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2022

The c.320G>A (p.R107H) alteration is located in exon 2 (coding exon 2) of the GJD2 gene. This alteration results from a G to A substitution at nucleotide position 320, causing the arginine (R) at amino acid position 107 to be replaced by a histidine (H). 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	0.19
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.28	D
MetaRNN	Uncertain	0.45	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.4	L
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.75
Sift	Benign	0.13	T
Sift4G	Uncertain	0.035	D
Polyphen		0.96	D
Vest4		0.31
MutPred		0.39		Loss of MoRF binding (P = 0.0477);
MVP		0.92
MPC		2.2
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.18
gMVP		0.76

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

Other links and lift over

dbSNP: rs1481161920; hg19: chr15-35045325;