NM_053277.3:c.128G>A

Variant names:

• chr21-34669516-G-A
• rs1301743676
• NM_053277.3:c.128G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_053277.3(CLIC6):​c.128G>A​(p.Gly43Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,038 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. G43A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.993
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050752044).

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.128G>A	p.Gly43Glu	missense	Exon 1 of 6	NP_444507.1	Q96NY7-2
	CLIC6	NM_001317009.2		c.128G>A	p.Gly43Glu	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.128G>A	p.Gly43Glu	missense	Exon 1 of 6	ENSP00000290332.4	Q96NY7-2
	CLIC6	ENST00000360731.7	TSL:1	c.128G>A	p.Gly43Glu	missense	Exon 1 of 7	ENSP00000353959.3	Q96NY7-1
	CLIC6	ENST00000954659.1		c.128G>A	p.Gly43Glu	missense	Exon 1 of 8	ENSP00000624718.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151974 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.00318

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089038 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 515158

African (AFR) AF: 0.00 AC: 0 AN: 22974

American (AMR) AF: 0.00 AC: 0 AN: 8426

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14592

East Asian (EAS) AF: 0.00 AC: 0 AN: 26558

South Asian (SAS) AF: 0.00 AC: 0 AN: 21480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21836

Middle Eastern (MID) AF: 0.000338 AC: 1 AN: 2956

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 926096

Other (OTH) AF: 0.00 AC: 0 AN: 44120

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.0042	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.99
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.0020
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.26		Gain of solvent accessibility (P = 0.0074)
MVP		0.12
MPC		1.9
ClinPred		0.043	T
GERP RS		-1.4
PromoterAI		0.010	Neutral
Varity_R		0.10
gMVP		0.094
Mutation Taster		=97/3	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: rs1301743676; hg19: chr21-36041815;