21-34669521-G-T

Variant names:

• chr21-34669521-G-T
• rs186952765
• NM_053277.3:c.133G>T

Variant summary

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

The NM_053277.3(CLIC6):​c.133G>T​(p.Glu45*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000184 in 1,088,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: CLIC6 NM_053277.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.133G>T	p.Glu45*	stop_gained	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.133G>T	p.Glu45*	stop_gained	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.133G>T	p.Glu45*	stop_gained	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.133G>T	p.Glu45*	stop_gained	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.133G>T	p.Glu45*	stop_gained	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000184 AC: 2 AN: 1088772 Hom.: 0 Cov.: 30 AF XY: 0.00000194 AC XY: 1 AN XY: 515008

African (AFR) AF: 0.00 AC: 0 AN: 22972

American (AMR) AF: 0.00 AC: 0 AN: 8416

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14602

East Asian (EAS) AF: 0.00 AC: 0 AN: 26546

South Asian (SAS) AF: 0.00 AC: 0 AN: 21482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2962

European-Non Finnish (NFE) AF: 0.00000216 AC: 2 AN: 925862

Other (OTH) AF: 0.00 AC: 0 AN: 44114

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.078	N
PhyloP100		0.46
Vest4		0.12
GERP RS		2.3
PromoterAI		0.0052	Neutral
Mutation Taster		=48/152	disease causing (fs/PTC)

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: rs186952765; hg19: chr21-36041820;