Genetic Variant GJB1:p.Leu90Leu (chrX-71223977-C-G) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_000166.6(GJB1):c.270C>G(p.Leu90Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,089,474 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. L90L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000028 ( 0 hom. 0 hem. )

Consequence

GJB1
NM_000166.6 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.27

Publications

0 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, MODERATE, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae)
X-linked progressive cerebellar ataxia
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

GJB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant X-71223977-C-G is Benign according to our data. Variant chrX-71223977-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1091864.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-2.27 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GJB1	NM_000166.6 link	c.270C>G	p.Leu90Leu	synonymous_variant	Exon 2 of 2	ENST00000361726.7	NP_000157.1	P08034A0A654ICJ7
GJB1	NM_001097642.3 link	c.270C>G	p.Leu90Leu	synonymous_variant	Exon 2 of 2		NP_001091111.1	P08034A0A654ICJ7
GJB1	NM_001440770.1 link	c.270C>G	p.Leu90Leu	synonymous_variant	Exon 3 of 3		NP_001427699.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GJB1	ENST00000361726.7 link	c.270C>G	p.Leu90Leu	synonymous_variant	Exon 2 of 2	1	NM_000166.6	ENSP00000354900.6		P08034

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000275

AC:

AN:

1089474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

356024

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26307

American (AMR)

AF:

0.00

AC:

AN:

34182

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19117

East Asian (EAS)

AF:

0.00

AC:

AN:

29953

South Asian (SAS)

AF:

0.00

AC:

AN:

52872

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.00000358

AC:

AN:

837048

Other (OTH)

AF:

0.00

AC:

AN:

45765

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth Neuropathy X

Benign:1

Aug 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

0.37

(source)

DANN

Benign

0.71

PhyloP100

-2.3

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over