chr17-40363058-C-G

Variant names:

• chr17-40363058-C-G
• rs532965992
• NM_152219.4:c.758G>C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_152219.4(GJD3):​c.758G>C​(p.Arg253Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,231,732 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (31 hom., cov: 32)
  • Exomes 𝑓: 0.022 (286 hom.)
• Consequence: GJD3 NM_152219.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.51

Genes affected

GJD3 (HGNC:19147): (gap junction protein delta 3) This gene is a member of the large family of connexins that are required for the formation of gap junctions. Six connexin monomers form a hemichannel, or connexon, on the cell surface. This connexon can interact with a connexon from a neighboring cell, thus forming a channel linking the cytoplasm of the 2 cells. [provided by RefSeq, Jul 2008]

GJD3-AS1 (HGNC:56092): (GJD3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004409313).
• BP6: Variant 17-40363058-C-G is Benign according to our data. Variant chr17-40363058-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3387757.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0152 (2287/150844) while in subpopulation NFE AF= 0.0228 (1541/67526). AF 95% confidence interval is 0.0219. There are 31 homozygotes in gnomad4. There are 1133 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJD3	NM_152219.4	c.758G>C	p.Arg253Pro	missense_variant	Exon 1 of 1	ENST00000578689.2	NP_689343.3
GJD3-AS1	NR_186704.1	n.214C>G		non_coding_transcript_exon_variant	Exon 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJD3	ENST00000578689.2	c.758G>C	p.Arg253Pro	missense_variant	Exon 1 of 1	6	NM_152219.4	ENSP00000463752.1
GJD3-AS1	ENST00000578774.1	n.484-25C>G		intron_variant	Intron 1 of 1	4

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2288 AN: 150734 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00407

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00492

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.0228

Gnomad OTH AF: 0.0155

GnomAD3 exomes AF: 0.0321 AC: 12 AN: 374 Hom.: 1 AF XY: 0.0229 AC XY: 5 AN XY: 218

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0316

Gnomad OTH exome AF: 0.100

GnomAD4 exome AF: 0.0223 AC: 24086 AN: 1080888 Hom.: 286 Cov.: 33 AF XY: 0.0224 AC XY: 11489 AN XY: 513114

Gnomad4 AFR exome AF: 0.00316

Gnomad4 AMR exome AF: 0.0130

Gnomad4 ASJ exome AF: 0.00541

Gnomad4 EAS exome AF: 0.0000385

Gnomad4 SAS exome AF: 0.00549

Gnomad4 FIN exome AF: 0.0207

Gnomad4 NFE exome AF: 0.0243

Gnomad4 OTH exome AF: 0.0192

GnomAD4 genome AF: 0.0152 AC: 2287 AN: 150844 Hom.: 31 Cov.: 32 AF XY: 0.0154 AC XY: 1133 AN XY: 73716

Gnomad4 AFR AF: 0.00406

Gnomad4 AMR AF: 0.0180

Gnomad4 ASJ AF: 0.00492

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.0226

Gnomad4 NFE AF: 0.0228

Gnomad4 OTH AF: 0.0153

Alfa AF: 0.0164 Hom.: 6

Bravo AF: 0.0139

ExAC AF: 0.00298 AC: 21

Asia WGS AF: 0.00233 AC: 8 AN: 3442

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Meniere disease Benign:1

Jan 09, 2024

Meniere Disease Neuroscience Research Program, Faculty of Medicine and Health, Kolling Institute, The University of Sydney

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

The NC_000017.11:g.40363058C>G, is a missense variant in GJD3 gene which produces an amino acid change from arginine to proline in the cytoplasmatic region of the connexon. The variant is part of an haplotype involved in Meniere’s Disease, composed by g.40356228C>T, g.40363058C>G, g.40363293G>A, g.40363294C>G and g.40363579G>T. The haplotype was found in 10 individuals with familial Meniere’s Disease, segregating in 3 of these families (PP1); and in another 8 individuals with sporadic Meniere’s Disease. GnomAD exomes allele frequency = 0.0223 is greater than 0.0001 (BS1); however, the frequency of the haplotype for the Iberian population in Spain is 0.0093. The variant was observed in healthy adults in gnomAD (BS2). The MetaRNN value of the variant is 0.0041 (BP4). In summary, this variant meets the criteria to be classified as likely benign based on the ACMG/AMP criteria applied: PP1,BS1,BS2,BP4. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	6.2
DANN	Benign	0.65
DEOGEN2	Benign	0.062	T
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0044	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.79	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.092
MPC		1.7
GERP RS		-1.6
Varity_R		0.14
gMVP		0.19

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: rs532965992; hg19: chr17-38519310;