21-34669543-G-T

Variant names:

• chr21-34669543-G-T
• rs749835973
• NM_053277.3:c.155G>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>T​(p.Arg52Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000715 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. R52K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (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=0.19891927).

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>T	p.Arg52Met	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.155G>T	p.Arg52Met	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>T	p.Arg52Met	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.155G>T	p.Arg52Met	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.155G>T	p.Arg52Met	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 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: 0.0000883

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000750 AC: 82 AN: 1093144 Hom.: 0 Cov.: 30 AF XY: 0.0000811 AC XY: 42 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: 0.0000872 AC: 81 AN: 928674

Other (OTH) AF: 0.0000226 AC: 1 AN: 44338

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152020 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 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: 0.0000883 AC: 6 AN: 67976

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

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	0.22
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	16
DANN	Benign	0.74
DEOGEN2	Benign	0.018	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.28	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		-0.18
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.059
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.016	D
Polyphen		0.95	P
Vest4		0.18
MutPred		0.37		Loss of methylation at R52 (P = 0.0295)
MVP		0.50
MPC		1.7
ClinPred		0.22	T
GERP RS		2.2
PromoterAI		0.062	Neutral
Varity_R		0.065
gMVP		0.24
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: rs749835973; hg19: chr21-36041842;