chr6-87284664-C-T

Position:

• chr6-87284664-C-T

Variant summary

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

The NM_198568.3(GJB7):​c.249G>A​(p.Met83Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,614,048 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (35 hom.)
• Consequence: GJB7 NM_198568.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.81

Genes affected

GJB7 (HGNC:16690): (gap junction protein beta 7) Connexins, such as GJB7, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

LOC124901356 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012876034).
• BP6: Variant 6-87284664-C-T is Benign according to our data. Variant chr6-87284664-C-T is described in ClinVar as [Benign]. Clinvar id is 712467.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.011 (1679/152164) while in subpopulation AFR AF= 0.037 (1535/41494). AF 95% confidence interval is 0.0355. There are 36 homozygotes in gnomad4. There are 801 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GJB7	NM_198568.3	c.249G>A	p.Met83Ile	missense_variant	3/3	ENST00000525899.6	NP_940970.1
LOC124901356	XR_007059667.1	n.730C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GJB7	ENST00000525899.6	c.249G>A	p.Met83Ile	missense_variant	3/3	1	NM_198568.3	ENSP00000435355.1
GJB7	ENST00000369576.2	c.249G>A	p.Met83Ile	missense_variant	2/2	4		ENSP00000358589.2

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1660 AN: 152046 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0366

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00602

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00334 AC: 838 AN: 251176 Hom.: 20 AF XY: 0.00242 AC XY: 329 AN XY: 135724

Gnomad AFR exome AF: 0.0395

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00576

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00139 AC: 2031 AN: 1461884 Hom.: 35 Cov.: 39 AF XY: 0.00124 AC XY: 905 AN XY: 727242

Gnomad4 AFR exome AF: 0.0392

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.00520

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000161

Gnomad4 OTH exome AF: 0.00396

GnomAD4 genome AF: 0.0110 AC: 1679 AN: 152164 Hom.: 36 Cov.: 32 AF XY: 0.0108 AC XY: 801 AN XY: 74382

Gnomad4 AFR AF: 0.0370

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00237 Hom.: 6

Bravo AF: 0.0126

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0359 AC: 158

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00408 AC: 495

Asia WGS AF: 0.00549 AC: 20 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000533

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;N
REVEL	Uncertain	0.44
Sift	Uncertain	0.018	D;D
Sift4G	Uncertain	0.033	D;.
Polyphen		0.63	P;.
Vest4		0.33
MutPred		0.69		Loss of catalytic residue at M83 (P = 0.1502);Loss of catalytic residue at M83 (P = 0.1502);
MVP		0.68
MPC		0.014
ClinPred		0.018	T
GERP RS		3.0
Varity_R		0.40
gMVP		0.49

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: rs73754173; hg19: chr6-87994382; COSMIC: COSV99032082;