1-34785360-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024009.3(GJB3):c.598G>C(p.Val200Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. V200I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GJB3 NM_024009.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05

Genes affected

GJB3 (HGNC:4285): (gap junction protein beta 3) This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

SMIM12 (HGNC:25154): (small integral membrane protein 12) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

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=0.22684896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GJB3	NM_024009.3	c.598G>C	p.Val200Leu	missense_variant	2/2	ENST00000373366.3
GJB3	NM_001005752.2	c.598G>C	p.Val200Leu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GJB3	ENST00000373366.3	c.598G>C	p.Val200Leu	missense_variant	2/2	1	NM_024009.3	P1
GJB3	ENST00000373362.3	c.598G>C	p.Val200Leu	missense_variant	2/2	1		P1
SMIM12	ENST00000426886.1	c.208-66951C>G		intron_variant, NMD_transcript_variant		1
	ENST00000542839.1	n.110+2628C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Benign	-0.14
Cadd	Benign	16
Dann	Benign	0.60
DEOGEN2	Benign	0.41	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.58
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.23	T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.76	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.57	N;N
REVEL	Uncertain	0.34
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.011	B;B
Vest4		0.20
MutPred		0.50		Loss of catalytic residue at V200 (P = 0.01);Loss of catalytic residue at V200 (P = 0.01);
MVP		0.84
MPC		0.29
ClinPred		0.11	T
GERP RS		2.1
Varity_R		0.063
gMVP		0.67

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: rs61734064; hg19: chr1-35250961;