Genetic Variant GJB1:p.Arg75Trp (chrX-71223930-C-T) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000166.6(GJB1):c.223C>T(p.Arg75Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

GJB1
NM_000166.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1O:1

Conservation

PhyloP100: 4.92

Publications

41 publications found

Variant links:

Genes affected

GJB1 (HGNC:4283): (gap junction protein beta 1) This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

GJB1 Gene-Disease associations (from GenCC):

Charcot-Marie-Tooth disease X-linked dominant 1
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
X-linked progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GJB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 28 uncertain in NM_000166.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-71223931-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 4 curated benign missense variants. Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Charcot-Marie-Tooth disease X-linked dominant 1, X-linked progressive cerebellar ataxia.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant X-71223930-C-T is Pathogenic according to our data. Variant chrX-71223930-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 21082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000166.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJB1	NM_000166.6	MANE Select	c.223C>T	p.Arg75Trp	missense	Exon 2 of 2	NP_000157.1	P08034
GJB1	NM_001097642.3		c.223C>T	p.Arg75Trp	missense	Exon 2 of 2	NP_001091111.1	P08034
GJB1	NM_001440770.1		c.223C>T	p.Arg75Trp	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GJB1	ENST00000361726.7	TSL:1 MANE Select	c.223C>T	p.Arg75Trp	missense	Exon 2 of 2	ENSP00000354900.6	P08034
GJB1	ENST00000374029.2	TSL:5	c.223C>T	p.Arg75Trp	missense	Exon 2 of 2	ENSP00000363141.1	P08034
GJB1	ENST00000447581.2	TSL:5	c.223C>T	p.Arg75Trp	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1092506

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

358516

African (AFR)

AF:

0.00

AC:

AN:

26332

American (AMR)

AF:

0.00

AC:

AN:

34449

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19289

East Asian (EAS)

AF:

0.00

AC:

AN:

30056

South Asian (SAS)

AF:

0.00

AC:

AN:

53213

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40180

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

838964

Other (OTH)

AF:

0.00

AC:

AN:

45893

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000261

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Charcot-Marie-Tooth disease X-linked dominant 1 (3)

Charcot-Marie-Tooth disease (1)

Charcot-Marie-Tooth Neuropathy X (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.70

BayesDel_noAF

Pathogenic

0.77

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.0

PhyloP100

4.9

PrimateAI

Pathogenic

0.86

PROVEAN

Pathogenic

-8.0

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.99

Gain of helix (P = 0.0696)

MVP

1.0

MPC

1.9

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

1.0

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over