21-34669629-G-T

Variant names:

• chr21-34669629-G-T
• rs927788428
• NM_053277.3:c.241G>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.241G>T​(p.Gly81Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000088 in 1,136,230 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G81S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• 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=0.07336855).

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.241G>T	p.Gly81Cys	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.241G>T	p.Gly81Cys	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.241G>T	p.Gly81Cys	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.241G>T	p.Gly81Cys	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.241G>T	p.Gly81Cys	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.80e-7 AC: 1 AN: 1136230 Hom.: 0 Cov.: 30 AF XY: 0.00000184 AC XY: 1 AN XY: 542816

African (AFR) AF: 0.00 AC: 0 AN: 23202

American (AMR) AF: 0.00 AC: 0 AN: 8710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15476

East Asian (EAS) AF: 0.00 AC: 0 AN: 26670

South Asian (SAS) AF: 0.0000287 AC: 1 AN: 34874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3078

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 952902

Other (OTH) AF: 0.00 AC: 0 AN: 46140

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.94
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-1.0
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.14
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0080	B
Vest4		0.12
MutPred		0.28		Gain of loop (P = 0.0097)
MVP		0.20
MPC		1.7
ClinPred		0.072	T
GERP RS		-2.7
PromoterAI		-0.0036	Neutral
Varity_R		0.12
gMVP		0.075
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: rs927788428; hg19: chr21-36041928;