21-34669803-G-A

Variant names:

• chr21-34669803-G-A
• rs1023371257
• NM_053277.3:c.415G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_053277.3(CLIC6):​c.415G>A​(p.Glu139Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000157 in 1,272,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: CLIC6 NM_053277.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.281

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.069915414).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLIC6	NM_053277.3	c.415G>A	p.Glu139Lys	missense_variant	Exon 1 of 6	ENST00000349499.3	NP_444507.1
CLIC6	NM_001317009.2	c.415G>A	p.Glu139Lys	missense_variant	Exon 1 of 7		NP_001303938.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLIC6	ENST00000349499.3	c.415G>A	p.Glu139Lys	missense_variant	Exon 1 of 6	1	NM_053277.3	ENSP00000290332.4
CLIC6	ENST00000360731.7	c.415G>A	p.Glu139Lys	missense_variant	Exon 1 of 7	1		ENSP00000353959.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000157 AC: 2 AN: 1272034 Hom.: 0 Cov.: 78 AF XY: 0.00 AC XY: 0 AN XY: 622078

Gnomad4 AFR exome AF: 0.0000410

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.69e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.415G>A (p.E139K) alteration is located in exon 1 (coding exon 1) of the CLIC6 gene. This alteration results from a G to A substitution at nucleotide position 415, causing the glutamic acid (E) at amino acid position 139 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.013	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.52	T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.070	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.94	N;N
REVEL	Benign	0.023
Sift	Benign	0.11	T;T
Sift4G	Uncertain	0.028	D;D
Polyphen		0.0080	B;B
Vest4		0.059
MutPred		0.24		Gain of ubiquitination at E139 (P = 0.009);Gain of ubiquitination at E139 (P = 0.009);
MVP		0.37
MPC		1.9
ClinPred		0.15	T
GERP RS		2.0
Varity_R		0.060
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1023371257; hg19: chr21-36042102;