chr1-11806318-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001286.5(CLCN6):​c.56G>T​(p.Gly19Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000735 in 1,361,128 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

CLCN6
NM_001286.5 missense

Scores

3
8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39
Variant links:
Genes affected
CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]
MTHFR (HGNC:7436): (methylenetetrahydrofolate reductase) The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CLCN6NM_001286.5 linkuse as main transcriptc.56G>T p.Gly19Val missense_variant 1/23 ENST00000346436.11 NP_001277.2
CLCN6NM_001256959.2 linkuse as main transcriptc.56G>T p.Gly19Val missense_variant 1/22 NP_001243888.2
CLCN6NR_046428.2 linkuse as main transcriptn.128G>T non_coding_transcript_exon_variant 1/23

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CLCN6ENST00000346436.11 linkuse as main transcriptc.56G>T p.Gly19Val missense_variant 1/231 NM_001286.5 ENSP00000234488 P1P51797-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.35e-7
AC:
1
AN:
1361128
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
675088
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.30e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 20, 2021In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CLCN6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 19 of the CLCN6 protein (p.Gly19Val). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
.;T;.
Eigen
Benign
-0.015
Eigen_PC
Benign
0.11
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
D;D;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Uncertain
0.45
T;T;T
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
1.4
L;L;L
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.81
D
PROVEAN
Benign
-0.60
N;N;N
REVEL
Uncertain
0.41
Sift
Uncertain
0.0010
D;D;D
Sift4G
Benign
0.22
T;T;D
Polyphen
0.0040, 0.40
.;B;B
Vest4
0.50
MutPred
0.20
Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);
MVP
0.86
MPC
0.42
ClinPred
0.92
D
GERP RS
4.1
Varity_R
0.27
gMVP
0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-11866375; COSMIC: COSV56739206; COSMIC: COSV56739206; API