13-20223180-C-G

Variant names:

• chr13-20223180-C-G
• rs571454176
• NM_001110219.3:c.301G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001110219.3(GJB6):​c.301G>C​(p.Glu101Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,613,064 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E101K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: GJB6 NM_001110219.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.20
• Publications: 9 publications found

Genes affected

GJB6 (HGNC:4288): (gap junction protein beta 6) Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

GJB6 Gene-Disease associations (from GenCC):

• Clouston syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, ClinGen, G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant nonsyndromic hearing loss 3B

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive nonsyndromic hearing loss 1B

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17013305).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000329 (48/1460914) while in subpopulation SAS AF = 0.000395 (34/86184). AF 95% confidence interval is 0.00029. There are 0 homozygotes in GnomAdExome4. There are 26 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001110219.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB6	NM_001110219.3	MANE Select	c.301G>C	p.Glu101Gln	missense	Exon 5 of 5	NP_001103689.1
	GJB6	NM_001110220.3		c.301G>C	p.Glu101Gln	missense	Exon 4 of 4	NP_001103690.1
	GJB6	NM_001110221.3		c.301G>C	p.Glu101Gln	missense	Exon 3 of 3	NP_001103691.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB6	ENST00000647029.1	MANE Select	c.301G>C	p.Glu101Gln	missense	Exon 5 of 5	ENSP00000493834.1
	GJB6	ENST00000241124.11	TSL:1	c.301G>C	p.Glu101Gln	missense	Exon 3 of 3	ENSP00000241124.6
	GJB6	ENST00000400065.7	TSL:1	c.301G>C	p.Glu101Gln	missense	Exon 3 of 3	ENSP00000382938.3

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250930 AF XY: 0.0000590

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1460914 Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26 AN XY: 726642

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.000395 AC: 34 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111300

Other (OTH) AF: 0.0000663 AC: 4 AN: 60360

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74328

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000576 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal dominant nonsyndromic hearing loss 3B (1)
-	1	-	Hidrotic ectodermal dysplasia syndrome;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675235:Autosomal recessive nonsyndromic hearing loss 1B;C2675237:Autosomal dominant nonsyndromic hearing loss 3B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.53
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.17	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Benign	0.85	L
PhyloP100		2.2
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.35
Sift	Benign	0.14	T
Sift4G	Benign	0.20	T
Polyphen		0.18	B
Vest4		0.23
MutPred		0.41		Gain of MoRF binding (P = 0.0286)
MVP		0.83
MPC		0.098
ClinPred		0.062	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.79
Mutation Taster		=86/14	polymorphism

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: rs571454176; hg19: chr13-20797319;