Genetic Variant CLIC6:p.Ala60Thr (chr21-34669566-G-A) – 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.178G>A(p.Ala60Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A60S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CLIC6
NM_053277.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.984

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=0.059836745).

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.178G>A	p.Ala60Thr	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.178G>A	p.Ala60Thr	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.178G>A	p.Ala60Thr	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
CLIC6	ENST00000360731.7	TSL:1	c.178G>A	p.Ala60Thr	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
CLIC6	ENST00000954659.1		c.178G>A	p.Ala60Thr	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1105828

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

525142

African (AFR)

AF:

0.00

AC:

AN:

23046

American (AMR)

AF:

0.00

AC:

AN:

8500

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14880

East Asian (EAS)

AF:

0.00

AC:

AN:

26610

South Asian (SAS)

AF:

0.00

AC:

AN:

25502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22882

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2990

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

936510

Other (OTH)

AF:

0.00

AC:

AN:

44908

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

Eigen

Benign

-0.81

Eigen_PC

Benign

-0.85

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.41

M_CAP

Benign

0.020

MetaRNN

Benign

0.060

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.98

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.51

REVEL

Benign

0.12

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.048

Polyphen

0.021

Vest4

0.065

MutPred

0.15

Gain of phosphorylation at A60 (P = 0.0106)

MVP

0.32

MPC

1.5

ClinPred

0.13

GERP RS

0.14

PromoterAI

-0.021

Neutral

(source)

Varity_R

0.097

gMVP

0.054

Mutation Taster

=98/2

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over