1-86430922-A-G

Variant names:

• chr1-86430922-A-G
• rs1251976492
• NM_006536.7:c.536A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006536.7(CLCA2):​c.536A>G​(p.Asn179Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLCA2 NM_006536.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.869

Genes affected

CLCA2 (HGNC:2016): (chloride channel accessory 2) This gene encodes a member of the calcium-activated chloride channel regulator (CLCR) family of proteins. Members of this family regulate the transport of chloride across the plasma membrane. The encoded protein is autoproteolytically processed to generate N- and C- terminal fragments. Expression of this gene is upregulated by the tumor suppressor protein p53 in response to DNA damage. In breast cancer, expression of this gene is downregulated and the encoded protein may inhibit migration and invasion while promoting mesenchymal-to-epithelial transition in cancer cell lines. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06096068).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCA2	NM_006536.7	c.536A>G	p.Asn179Ser	missense_variant	Exon 4 of 14	ENST00000370565.5	NP_006527.1
CLCA2	XM_011542448.4	c.536A>G	p.Asn179Ser	missense_variant	Exon 4 of 11		XP_011540750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCA2	ENST00000370565.5	c.536A>G	p.Asn179Ser	missense_variant	Exon 4 of 14	1	NM_006536.7	ENSP00000359596.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250884 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135604

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.536A>G (p.N179S) alteration is located in exon 4 (coding exon 4) of the CLCA2 gene. This alteration results from a A to G substitution at nucleotide position 536, causing the asparagine (N) at amino acid position 179 to be replaced by a serine (S). 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	0.059
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.8
DANN	Benign	0.83
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.069	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.041
Sift	Benign	0.46	T
Sift4G	Benign	0.64	T
Polyphen		0.0070	B
Vest4		0.13
MutPred		0.42		Loss of stability (P = 0.043);
MVP		0.088
MPC		0.067
ClinPred		0.041	T
GERP RS		2.3
Varity_R		0.054
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs1251976492; hg19: chr1-86896605;