chr15-34753121-C-A

Variant names:

• chr15-34753121-C-A
• rs780722117
• NM_020660.3:c.323G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020660.3(GJD2):​c.323G>T​(p.Arg108Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GJD2 NM_020660.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.85
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3091302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD2	NM_020660.3	c.323G>T	p.Arg108Leu	missense_variant	Exon 2 of 2	ENST00000290374.5	NP_065711.1
GJD2	XM_017022438.2	c.170G>T	p.Arg57Leu	missense_variant	Exon 2 of 2		XP_016877927.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJD2	ENST00000290374.5	c.323G>T	p.Arg108Leu	missense_variant	Exon 2 of 2	1	NM_020660.3	ENSP00000290374.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461860 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.31	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.9
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.58
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.019	D
Polyphen		0.028	B
Vest4		0.40
MutPred		0.35		Loss of phosphorylation at T111 (P = 0.0445);
MVP		0.80
MPC		1.6
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.30
gMVP		0.87

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: rs780722117; hg19: chr15-35045322; COSMIC: COSV99290937; COSMIC: COSV99290937;