chr21-34669836-G-A

Position:

• chr21-34669836-G-A

Variant summary

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

The NM_053277.3(CLIC6):​c.448G>A​(p.Gly150Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000158 in 1,264,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.83

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=0.09728429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC6	NM_053277.3	c.448G>A	p.Gly150Ser	missense_variant	1/6	ENST00000349499.3
CLIC6	NM_001317009.2	c.448G>A	p.Gly150Ser	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC6	ENST00000349499.3	c.448G>A	p.Gly150Ser	missense_variant	1/6	1	NM_053277.3	P2
CLIC6	ENST00000360731.7	c.448G>A	p.Gly150Ser	missense_variant	1/7	1		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000158 AC: 2 AN: 1264240 Hom.: 0 Cov.: 79 AF XY: 0.00000324 AC XY: 2 AN XY: 616554

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000684

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.48	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.20	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.026
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.089	T;T
Polyphen		0.62	P;P
Vest4		0.096
MutPred		0.15		Gain of phosphorylation at G150 (P = 0.0071);Gain of phosphorylation at G150 (P = 0.0071);
MVP		0.34
MPC		2.8
ClinPred		0.27	T
GERP RS		0.89
Varity_R		0.082
gMVP		0.035

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1398123470; hg19: chr21-36042135; COSMIC: COSV62447755;