1-86428451-C-T

Variant names:

• chr1-86428451-C-T
• rs1662430345
• NM_006536.7:c.358C>T

Variant summary

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

The NM_006536.7(CLCA2):​c.358C>T​(p.His120Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000754 in 1,458,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H120R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: CLCA2 NM_006536.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.193

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=0.055714667).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCA2	NM_006536.7	c.358C>T	p.His120Tyr	missense_variant	Exon 3 of 14	ENST00000370565.5	NP_006527.1
CLCA2	XM_011542448.4	c.358C>T	p.His120Tyr	missense_variant	Exon 3 of 11		XP_011540750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCA2	ENST00000370565.5	c.358C>T	p.His120Tyr	missense_variant	Exon 3 of 14	1	NM_006536.7	ENSP00000359596.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000754 AC: 11 AN: 1458524 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725394

Gnomad4 AFR exome AF: 0.00

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: 0.00000991

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.358C>T (p.H120Y) alteration is located in exon 3 (coding exon 3) of the CLCA2 gene. This alteration results from a C to T substitution at nucleotide position 358, causing the histidine (H) at amino acid position 120 to be replaced by a tyrosine (Y). 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	0.064
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	5.5
DANN	Benign	0.44
DEOGEN2	Benign	0.045	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.072	T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.27	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.087
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.36
MutPred		0.53		Loss of disorder (P = 0.0809);
MVP		0.072
MPC		0.077
ClinPred		0.043	T
GERP RS		1.2
Varity_R		0.043
gMVP		0.34

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: rs1662430345; hg19: chr1-86894134;