Genetic Variant NM_000166.6:c.235C>T (chrX-71223942-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000166.6(GJB1):c.235C>T(p.Leu79Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.00246 in 1,203,224 control chromosomes in the GnomAD database, including 3 homozygotes. There are 924 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., 55 hem., cov: 22)

Exomes 𝑓: 0.0025 ( 3 hom. 869 hem. )

Consequence

GJB1
NM_000166.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2B:11

Conservation

PhyloP100: 5.00

Publications

2 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant X-71223942-C-T is Benign according to our data. Variant chrX-71223942-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 220932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00184 (205/111213) while in subpopulation NFE AF = 0.00266 (141/52947). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 55 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 55 XL gene

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.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	NP_000157.1	P08034
GJB1	NM_001097642.3		c.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	NP_001091111.1	P08034
GJB1	NM_001440770.1		c.235C>T	p.Leu79Leu	synonymous	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.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	ENSP00000354900.6	P08034
GJB1	ENST00000374029.2	TSL:5	c.235C>T	p.Leu79Leu	synonymous	Exon 2 of 2	ENSP00000363141.1	P08034
GJB1	ENST00000447581.2	TSL:5	c.235C>T	p.Leu79Leu	synonymous	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes

AF:

0.00184

AC:

205

AN:

111161

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000262

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000384

Gnomad ASJ

AF:

0.00944

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00400

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00200

GnomAD2 exomes

AF:

0.00237

AC:

396

AN:

167208

AF XY:

0.00216

show subpopulations

Gnomad AFR exome

AF:

0.000408

Gnomad AMR exome

AF:

0.000812

Gnomad ASJ exome

AF:

0.00721

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00463

Gnomad NFE exome

AF:

0.00328

Gnomad OTH exome

AF:

0.00283

GnomAD4 exome

AF:

0.00252

AC:

2752

AN:

1092011

Hom.:

Cov.:

AF XY:

0.00243

AC XY:

869

AN XY:

358185

show subpopulations

African (AFR)

AF:

0.000494

AC:

AN:

26335

American (AMR)

AF:

0.000817

AC:

AN:

34292

Ashkenazi Jewish (ASJ)

AF:

0.00904

AC:

174

AN:

19255

East Asian (EAS)

AF:

0.00

AC:

AN:

30022

South Asian (SAS)

AF:

0.00

AC:

AN:

53178

European-Finnish (FIN)

AF:

0.00496

AC:

199

AN:

40151

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00268

AC:

2252

AN:

838776

Other (OTH)

AF:

0.00183

AC:

AN:

45872

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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

AF:

0.00184

AC:

205

AN:

111213

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

AN XY:

33455

show subpopulations

African (AFR)

AF:

0.000261

AC:

AN:

30637

American (AMR)

AF:

0.000383

AC:

AN:

10439

Ashkenazi Jewish (ASJ)

AF:

0.00944

AC:

AN:

2648

East Asian (EAS)

AF:

0.00

AC:

AN:

3502

South Asian (SAS)

AF:

0.00

AC:

AN:

2625

European-Finnish (FIN)

AF:

0.00400

AC:

AN:

5996

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00266

AC:

141

AN:

52947

Other (OTH)

AF:

0.00197

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00359

Hom.:

Bravo

AF:

0.00160

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

not specified (2)

Charcot-Marie-Tooth Neuropathy X (1)

Dejerine-Sottas disease (1)

GJB1-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.6

(source)

DANN

Benign

0.72

PhyloP100

5.0

Mutation Taster

=89/11

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over