21-34669997-G-C

Position:

• chr21-34669997-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053277.3(CLIC6):​c.609G>C​(p.Glu203Asp) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0250

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.107682824).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC6	NM_053277.3	c.609G>C	p.Glu203Asp	missense_variant	1/6	ENST00000349499.3
CLIC6	NM_001317009.2	c.609G>C	p.Glu203Asp	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC6	ENST00000349499.3	c.609G>C	p.Glu203Asp	missense_variant	1/6	1	NM_053277.3	P2
CLIC6	ENST00000360731.7	c.609G>C	p.Glu203Asp	missense_variant	1/7	1		A2

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 25, 2022

The c.609G>C (p.E203D) alteration is located in exon 1 (coding exon 1) of the CLIC6 gene. This alteration results from a G to C substitution at nucleotide position 609, causing the glutamic acid (E) at amino acid position 203 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.23	N;N
REVEL	Benign	0.061
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.90	P;P
Vest4		0.074
MutPred		0.11		Gain of glycosylation at S199 (P = 0.2235);Gain of glycosylation at S199 (P = 0.2235);
MVP		0.38
MPC		1.5
ClinPred		0.11	T
GERP RS		0.64
Varity_R		0.098
gMVP		0.049

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

LitVar

Other links and lift over

dbSNP: rs1989508054; hg19: chr21-36042296;