21-34669926-G-C

Variant names:

• chr21-34669926-G-C
• NM_053277.3:c.538G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.375

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=0.054353833).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC6	NM_053277.3	c.538G>C	p.Val180Leu	missense_variant	Exon 1 of 6	ENST00000349499.3	NP_444507.1
CLIC6	NM_001317009.2	c.538G>C	p.Val180Leu	missense_variant	Exon 1 of 7		NP_001303938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC6	ENST00000349499.3	c.538G>C	p.Val180Leu	missense_variant	Exon 1 of 6	1	NM_053277.3	ENSP00000290332.4
CLIC6	ENST00000360731.7	c.538G>C	p.Val180Leu	missense_variant	Exon 1 of 7	1		ENSP00000353959.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1163264 Hom.: 0 Cov.: 65 AF XY: 0.00 AC XY: 0 AN XY: 562178

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: 0.00000208

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.1
DANN	Benign	0.85
DEOGEN2	Benign	0.022	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.30	T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.44	N;N
REVEL	Benign	0.0050
Sift	Benign	0.079	T;T
Sift4G	Uncertain	0.037	D;D
Polyphen		0.17	B;B
Vest4		0.11
MutPred		0.13		Gain of glycosylation at S179 (P = 0.1443);Gain of glycosylation at S179 (P = 0.1443);
MVP		0.27
MPC		2.0
ClinPred		0.050	T
GERP RS		-0.26
Varity_R		0.046
gMVP		0.046

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: chr21-36042225;