21-34670043-A-G

Position:

• chr21-34670043-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_053277.3(CLIC6):​c.655A>G​(p.Ser219Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 27)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.69

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.055075347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLIC6	NM_053277.3	c.655A>G	p.Ser219Gly	missense_variant	1/6	ENST00000349499.3
CLIC6	NM_001317009.2	c.655A>G	p.Ser219Gly	missense_variant	1/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLIC6	ENST00000349499.3	c.655A>G	p.Ser219Gly	missense_variant	1/6	1	NM_053277.3	P2
CLIC6	ENST00000360731.7	c.655A>G	p.Ser219Gly	missense_variant	1/7	1		A2

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 133090 Hom.: 0 Cov.: 27 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1163562 Hom.: 0 Cov.: 65 AF XY: 0.00 AC XY: 0 AN XY: 560662

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 133090 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 64090

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.6
DANN	Benign	0.67
DEOGEN2	Benign	0.015	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0018	N
LIST_S2	Benign	0.33	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.055	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.0060
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.81	T;T
Polyphen		0.0010	B;B
Vest4		0.087
MutPred		0.12		Loss of phosphorylation at S219 (P = 0.021);Loss of phosphorylation at S219 (P = 0.021);
MVP		0.15
MPC		1.5
ClinPred		0.057	T
GERP RS		-5.8
Varity_R		0.086
gMVP		0.082

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: rs1601253958; hg19: chr21-36042342;