15-34752912-G-C

Variant names:

• chr15-34752912-G-C
• rs1234431704
• NM_020660.3:c.532C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020660.3(GJD2):​c.532C>G​(p.Pro178Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 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. P178S) 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: 6.90
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21402398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD2	NM_020660.3	c.532C>G	p.Pro178Ala	missense_variant	Exon 2 of 2	ENST00000290374.5	NP_065711.1
GJD2	XM_017022438.2	c.379C>G	p.Pro127Ala	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.532C>G	p.Pro178Ala	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: 1461848 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 727226

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: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Uncertain	0.59	D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.1	L
PhyloP100		6.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.29
Sift	Benign	0.099	T
Sift4G	Benign	0.11	T
Polyphen		0.068	B
Vest4		0.19
MutPred		0.23		Gain of MoRF binding (P = 0.0541);
MVP		0.79
MPC		0.91
ClinPred		0.22	T
GERP RS		4.2
Varity_R		0.052
gMVP		0.40

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: rs1234431704; hg19: chr15-35045113;