chr21-34669898-A-G

Variant names:

• chr21-34669898-A-G
• rs1343412139
• NM_053277.3:c.510A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053277.3(CLIC6):​c.510A>G​(p.Ile170Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000256 in 1,172,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.77
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033156246).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_053277.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC6	NM_053277.3	MANE Select	c.510A>G	p.Ile170Met	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.510A>G	p.Ile170Met	missense	Exon 1 of 7	NP_001303938.1	Q96NY7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLIC6	ENST00000349499.3	TSL:1 MANE Select	c.510A>G	p.Ile170Met	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.510A>G	p.Ile170Met	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.510A>G	p.Ile170Met	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes AF: 0.0000135 AC: 2 AN: 148238 Hom.: 0 Cov.: 32

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: 0.0000298

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000256 AC: 3 AN: 1172962 Hom.: 0 Cov.: 78 AF XY: 0.00000528 AC XY: 3 AN XY: 568102

African (AFR) AF: 0.00 AC: 0 AN: 22118

American (AMR) AF: 0.00 AC: 0 AN: 13306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14578

East Asian (EAS) AF: 0.0000453 AC: 1 AN: 22080

South Asian (SAS) AF: 0.00 AC: 0 AN: 56560

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3080

European-Non Finnish (NFE) AF: 0.00000206 AC: 2 AN: 968936

Other (OTH) AF: 0.00 AC: 0 AN: 46676

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000135 AC: 2 AN: 148330 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 1 AN XY: 72416

African (AFR) AF: 0.00 AC: 0 AN: 39716

American (AMR) AF: 0.00 AC: 0 AN: 15058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 4908

South Asian (SAS) AF: 0.00 AC: 0 AN: 4670

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10144

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 270

European-Non Finnish (NFE) AF: 0.0000298 AC: 2 AN: 67116

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.61
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0025	N
LIST_S2	Benign	0.21	T
M_CAP	Benign	0.0015	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		-1.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.033
Sift	Benign	1.0	T
Sift4G	Uncertain	0.043	D
Polyphen		0.0020	B
Vest4		0.068
MutPred		0.17		Loss of catalytic residue at L166 (P = 0.4231)
MVP		0.099
MPC		1.8
ClinPred		0.047	T
GERP RS		-3.7
Varity_R		0.050
gMVP		0.019
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs1343412139; hg19: chr21-36042197;