Variant chr1-86428452-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006536.7(CLCA2):c.359A>G(p.His120Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,459,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H120Y) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CLCA2
NM_006536.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Variant links:

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]

CLCA2 links:

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ACMG classification

Classification made for transcript

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=0.09765899).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCA2	NM_006536.7 linkuse as main transcript	c.359A>G	p.His120Arg	missense_variant	3/14	ENST00000370565.5
CLCA2	XM_011542448.4 linkuse as main transcript	c.359A>G	p.His120Arg	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCA2	ENST00000370565.5 linkuse as main transcript	c.359A>G	p.His120Arg	missense_variant	3/14	1	NM_006536.7	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000442

AC:

AN:

249002

Hom.:

AF XY:

0.0000743

AC XY:

AN XY:

134580

show subpopulations

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:

0.000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000887

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1459634

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

726016

show subpopulations

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:

0.000361

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

The c.359A>G (p.H120R) alteration is located in exon 3 (coding exon 3) of the CLCA2 gene. This alteration results from a A to G substitution at nucleotide position 359, causing the histidine (H) at amino acid position 120 to be replaced by an arginine (R). 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

0.056

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.23

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.39

LIST_S2

Benign

0.046

M_CAP

Benign

0.0037

MetaRNN

Benign

0.098

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

MutationTaster

Benign

0.99

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.033

Sift

Benign

0.36

Sift4G

Benign

0.34

Polyphen

0.33

Vest4

0.32

MutPred

0.49

Gain of solvent accessibility (P = 0.0044);

MVP

0.13

MPC

0.081

ClinPred

0.13

GERP RS

1.7

Varity_R

0.083

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over