Genetic Variant NM_053277.3:c.538G>C (chr21-34669926-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_053277.3(CLIC6):c.538G>C(p.Val180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000172 in 1,163,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. V180V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000017 ( 0 hom. )

Consequence

CLIC6
NM_053277.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.375

Publications

0 publications found

Variant links:

Genes affected

CLIC6 (HGNC:2065): (chloride intracellular channel 6) This gene encodes a member of the chloride intracellular channel family of proteins. The gene is part of a large triplicated region found on chromosomes 1, 6, and 21. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Nov 2015]

CLIC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054353833).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053277.3. 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
	CLIC6	NM_053277.3	MANE Select	c.538G>C	p.Val180Leu	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.538G>C	p.Val180Leu	missense	Exon 1 of 7	NP_001303938.1	Q96NY7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLIC6	ENST00000349499.3	TSL:1 MANE Select	c.538G>C	p.Val180Leu	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
CLIC6	ENST00000360731.7	TSL:1	c.538G>C	p.Val180Leu	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
CLIC6	ENST00000954659.1		c.538G>C	p.Val180Leu	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000172

AC:

AN:

1163264

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

562178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22162

American (AMR)

AF:

0.00

AC:

AN:

12038

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14430

East Asian (EAS)

AF:

0.00

AC:

AN:

21594

South Asian (SAS)

AF:

0.00

AC:

AN:

54734

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25536

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3068

European-Non Finnish (NFE)

AF:

0.00000208

AC:

AN:

963440

Other (OTH)

AF:

0.00

AC:

AN:

46262

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

6.1

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.022

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.013

LIST_S2

Benign

0.30

M_CAP

Benign

0.025

MetaRNN

Benign

0.054

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

-0.38

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.44

REVEL

Benign

0.0050

Sift

Benign

0.079

Sift4G

Uncertain

0.037

Polyphen

0.17

Vest4

0.11

MutPred

0.13

Gain of glycosylation at S179 (P = 0.1443)

MVP

0.27

MPC

2.0

ClinPred

0.050

GERP RS

-0.26

Varity_R

0.046

gMVP

0.046

Mutation Taster

=99/1

polymorphism

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over