chr21-34670029-G-T

Position:

• chr21-34670029-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053277.3(CLIC6):​c.641G>T​(p.Gly214Val) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 27)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.150

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055509925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC6	NM_053277.3	c.641G>T	p.Gly214Val	missense_variant	1/6	ENST00000349499.3
CLIC6	NM_001317009.2	c.641G>T	p.Gly214Val	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC6	ENST00000349499.3	c.641G>T	p.Gly214Val	missense_variant	1/6	1	NM_053277.3	P2
CLIC6	ENST00000360731.7	c.641G>T	p.Gly214Val	missense_variant	1/7	1		A2

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 27

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

sellar metastasis from primary bronchial carcinoid tumor Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Neurosurgery, Yale University School of Medicine

Feb 06, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	8.4
DANN	Benign	0.92
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.35	T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.056	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.040	N;N
REVEL	Benign	0.012
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.23	B;B
Vest4		0.10
MutPred		0.16		Loss of catalytic residue at G214 (P = 0.0532);Loss of catalytic residue at G214 (P = 0.0532);
MVP		0.23
MPC		2.7
ClinPred		0.16	T
GERP RS		-1.0
Varity_R		0.056
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1989509304; hg19: chr21-36042328;