rs104894825

Variant names:

• chrX-71224411-T-G
• rs104894825
• NM_000166.6:c.704T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000166.6(GJB1):​c.704T>G​(p.Phe235Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,208,238 control chromosomes in the GnomAD database, including 1 homozygotes. There are 144 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F235L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., 67 hem., cov: 21)
  • Exomes 𝑓: 0.00029 (0 hom. 77 hem.)
• Consequence: GJB1 NM_000166.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:8 O:1
• Conservation: PhyloP100: 1.98
• Publications: 21 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a chain Gap junction beta-1 protein (size 282) in uniprot entity CXB1_HUMAN there are 184 pathogenic changes around while only 11 benign (94%) in NM_000166.6
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.03338042).
• BP6: Variant X-71224411-T-G is Benign according to our data. Variant chrX-71224411-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10450.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00277 (309/111458) while in subpopulation AFR AF = 0.00949 (291/30648). AF 95% confidence interval is 0.0086. There are 1 homozygotes in GnomAd4. There are 67 alleles in the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 67 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	NM_000166.6	MANE Select	c.704T>G	p.Phe235Cys	missense	Exon 2 of 2	NP_000157.1	P08034
	GJB1	NM_001097642.3		c.704T>G	p.Phe235Cys	missense	Exon 2 of 2	NP_001091111.1	P08034
	GJB1	NM_001440770.1		c.704T>G	p.Phe235Cys	missense	Exon 3 of 3	NP_001427699.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GJB1	ENST00000361726.7	TSL:1 MANE Select	c.704T>G	p.Phe235Cys	missense	Exon 2 of 2	ENSP00000354900.6	P08034
	GJB1	ENST00000374029.2	TSL:5	c.704T>G	p.Phe235Cys	missense	Exon 2 of 2	ENSP00000363141.1	P08034
	GJB1	ENST00000447581.2	TSL:5	c.704T>G	p.Phe235Cys	missense	Exon 3 of 3	ENSP00000407223.2	P08034

Frequencies

GnomAD3 genomes AF: 0.00277 AC: 309 AN: 111403 Hom.: 1 Cov.: 21

Gnomad AFR AF: 0.00952

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

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: 0.0000189

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.000727 AC: 129 AN: 177535 AF XY: 0.000411

Gnomad AFR exome AF: 0.00888

Gnomad AMR exome AF: 0.000442

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000632

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.000286 AC: 314 AN: 1096780 Hom.: 0 Cov.: 32 AF XY: 0.000213 AC XY: 77 AN XY: 362278

African (AFR) AF: 0.00970 AC: 256 AN: 26386

American (AMR) AF: 0.000512 AC: 18 AN: 35142

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00 AC: 0 AN: 53893

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39991

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4136

European-Non Finnish (NFE) AF: 0.0000154 AC: 13 AN: 841643

Other (OTH) AF: 0.000565 AC: 26 AN: 46052

GnomAD4 genome AF: 0.00277 AC: 309 AN: 111458 Hom.: 1 Cov.: 21 AF XY: 0.00199 AC XY: 67 AN XY: 33654

African (AFR) AF: 0.00949 AC: 291 AN: 30648

American (AMR) AF: 0.00133 AC: 14 AN: 10536

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3511

South Asian (SAS) AF: 0.00 AC: 0 AN: 2643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6036

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000189 AC: 1 AN: 53029

Other (OTH) AF: 0.00198 AC: 3 AN: 1515

Alfa AF: 0.00116 Hom.: 6

Bravo AF: 0.00308

ESP6500AA AF: 0.00834 AC: 32

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000783 AC: 95

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	2	Charcot-Marie-Tooth disease X-linked dominant 1 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth Neuropathy X (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	21
DANN	Benign	0.66
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.033	T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	0.34	N
PhyloP100		2.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	0.48	N
REVEL	Uncertain	0.38
Sift	Benign	0.17	T
Sift4G	Benign	0.17	T
Polyphen		0.80	P
Vest4		0.72
MVP		0.89
MPC		1.3
ClinPred		0.038	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.78
Mutation Taster		=86/14	polymorphism (auto)

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: rs104894825; hg19: chrX-70444261;