rs749835973

Variant names:

• chr21-34669543-G-A
• rs749835973
• NM_053277.3:c.155G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-34669543-G-A
• chr21-34669543-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053277.3(CLIC6):​c.155G>A​(p.Arg52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000956 in 1,245,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R52M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.179
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06931263).

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.155G>A	p.Arg52Lys	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.155G>A	p.Arg52Lys	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.155G>A	p.Arg52Lys	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.155G>A	p.Arg52Lys	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.155G>A	p.Arg52Lys	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152020 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 116 AF XY: 0.00

Gnomad AMR exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000101 AC: 110 AN: 1093144 Hom.: 0 Cov.: 30 AF XY: 0.000100 AC XY: 52 AN XY: 517708

African (AFR) AF: 0.00 AC: 0 AN: 22984

American (AMR) AF: 0.00 AC: 0 AN: 8434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14662

East Asian (EAS) AF: 0.00 AC: 0 AN: 26564

South Asian (SAS) AF: 0.00 AC: 0 AN: 22456

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 22060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2972

European-Non Finnish (NFE) AF: 0.000115 AC: 107 AN: 928674

Other (OTH) AF: 0.0000677 AC: 3 AN: 44338

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152020 Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4 AN XY: 74272

African (AFR) AF: 0.0000242 AC: 1 AN: 41400

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000529 Hom.: 0

Bravo AF: 0.0000642

ExAC AF: 0.0000301 AC: 1

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	0.095
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.32	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.18
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.0050
Sift	Benign	0.045	D
Sift4G	Benign	0.17	T
Polyphen		0.035	B
Vest4		0.035
MVP		0.26
MPC		1.6
ClinPred		0.10	T
GERP RS		2.2
PromoterAI		0.069	Neutral
Varity_R		0.059
gMVP		0.12
Mutation Taster		=93/7	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: rs749835973; hg19: chr21-36041842;