rs201318042

Variant names:

• chr21-34669926-G-T
• rs201318042
• NM_053277.3:c.538G>T

Your query was ambiguous. Multiple possible variants found:

• chr21-34669926-G-T
• chr21-34669926-G-A
• chr21-34669926-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_053277.3(CLIC6):​c.538G>T​(p.Val180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,313,850 control chromosomes in the GnomAD database, including 33 homozygotes. 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V180V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0072 (21 hom., cov: 30)
  • Exomes 𝑓: 0.00074 (12 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.375
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026577115).
• BP6: Variant 21-34669926-G-T is Benign according to our data. Variant chr21-34669926-G-T is described in ClinVar as Benign. ClinVar VariationId is 710983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00724 (1091/150588) while in subpopulation AFR AF = 0.025 (1023/40880). AF 95% confidence interval is 0.0238. There are 21 homozygotes in GnomAd4. There are 513 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

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.538G>T	p.Val180Leu	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.538G>T	p.Val180Leu	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.538G>T	p.Val180Leu	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.538G>T	p.Val180Leu	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.538G>T	p.Val180Leu	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes AF: 0.00724 AC: 1089 AN: 150466 Hom.: 21 Cov.: 30

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

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: 0.0000148

Gnomad OTH AF: 0.00242

GnomAD2 exomes AF: 0.000159 AC: 3 AN: 18914 AF XY: 0.00

Gnomad AFR exome AF: 0.00196

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000736 AC: 856 AN: 1163262 Hom.: 12 Cov.: 65 AF XY: 0.000653 AC XY: 367 AN XY: 562176

African (AFR) AF: 0.0321 AC: 712 AN: 22160

American (AMR) AF: 0.00208 AC: 25 AN: 12038

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14430

East Asian (EAS) AF: 0.00 AC: 0 AN: 21594

South Asian (SAS) AF: 0.0000365 AC: 2 AN: 54734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25536

Middle Eastern (MID) AF: 0.000652 AC: 2 AN: 3068

European-Non Finnish (NFE) AF: 0.0000187 AC: 18 AN: 963440

Other (OTH) AF: 0.00210 AC: 97 AN: 46262

GnomAD4 genome AF: 0.00724 AC: 1091 AN: 150588 Hom.: 21 Cov.: 30 AF XY: 0.00697 AC XY: 513 AN XY: 73610

African (AFR) AF: 0.0250 AC: 1023 AN: 40880

American (AMR) AF: 0.00407 AC: 62 AN: 15220

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5042

South Asian (SAS) AF: 0.00 AC: 0 AN: 4740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10462

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67510

Other (OTH) AF: 0.00239 AC: 5 AN: 2092

Alfa AF: 0.00124 Hom.: 0

ExAC AF: 0.000788 AC: 76

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.2
DANN	Benign	0.85
DEOGEN2	Benign	0.022	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.38
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.0030
Sift	Benign	0.079	T
Sift4G	Uncertain	0.037	D
Polyphen		0.17	B
Vest4		0.11
MutPred		0.13		Gain of glycosylation at S179 (P = 0.1443)
MVP		0.27
MPC		2.0
ClinPred		0.0048	T
GERP RS		-0.26
Varity_R		0.046
gMVP		0.046
Mutation Taster		=99/1	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: rs201318042; hg19: chr21-36042225; COSMIC: COSV62447585;