Genetic Variant CLCA2:c.476-4G>A (chr1-86430858-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006536.7(CLCA2):c.476-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 1,609,854 control chromosomes in the GnomAD database, including 102,121 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 8802 hom., cov: 32)

Exomes 𝑓: 0.36 ( 93319 hom. )

Consequence

CLCA2
NM_006536.7 splice_region, intron

Scores

Splicing: ADA: 0.00007262

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.945

Publications

23 publications found

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 Gene-Disease associations (from GenCC):

heart conduction disease
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp

CLCA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCA2	NM_006536.7 link	c.476-4G>A		splice_region_variant, intron_variant	Intron 3 of 13	ENST00000370565.5	NP_006527.1	Q9UQC9
CLCA2	XM_011542448.4 link	c.476-4G>A		splice_region_variant, intron_variant	Intron 3 of 10		XP_011540750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLCA2	ENST00000370565.5 link	c.476-4G>A		splice_region_variant, intron_variant	Intron 3 of 13	1	NM_006536.7	ENSP00000359596.4		Q9UQC9

Frequencies

GnomAD3 genomes

AF:

0.337

AC:

51178

AN:

151896

Hom.:

8797

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.523

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.306

Gnomad EAS

AF:

0.510

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.358

Gnomad NFE

AF:

0.343

Gnomad OTH

AF:

0.298

GnomAD2 exomes

AF:

0.356

AC:

88497

AN:

248838

AF XY:

0.359

show subpopulations

Gnomad AFR exome

AF:

0.306

Gnomad AMR exome

AF:

0.315

Gnomad ASJ exome

AF:

0.303

Gnomad EAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.353

Gnomad NFE exome

AF:

0.344

Gnomad OTH exome

AF:

0.345

GnomAD4 exome

AF:

0.356

AC:

518579

AN:

1457840

Hom.:

93319

Cov.:

AF XY:

0.357

AC XY:

259049

AN XY:

725222

show subpopulations

African (AFR)

AF:

0.304

AC:

10131

AN:

33302

American (AMR)

AF:

0.312

AC:

13759

AN:

44114

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

7945

AN:

26050

East Asian (EAS)

AF:

0.493

AC:

19528

AN:

39588

South Asian (SAS)

AF:

0.406

AC:

34752

AN:

85528

European-Finnish (FIN)

AF:

0.345

AC:

18447

AN:

53402

Middle Eastern (MID)

AF:

0.357

AC:

2055

AN:

5752

European-Non Finnish (NFE)

AF:

0.352

AC:

390457

AN:

1109862

Other (OTH)

AF:

0.357

AC:

21505

AN:

60242

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

16276

32553

48829

65106

81382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12620

25240

37860

50480

63100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.337

AC:

51207

AN:

152014

Hom.:

8802

Cov.:

AF XY:

0.336

AC XY:

24953

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.305

AC:

12654

AN:

41448

American (AMR)

AF:

0.304

AC:

4646

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

1059

AN:

3466

East Asian (EAS)

AF:

0.511

AC:

2625

AN:

5140

South Asian (SAS)

AF:

0.408

AC:

1965

AN:

4818

European-Finnish (FIN)

AF:

0.351

AC:

3710

AN:

10574

Middle Eastern (MID)

AF:

0.361

AC:

106

AN:

294

European-Non Finnish (NFE)

AF:

0.343

AC:

23336

AN:

67976

Other (OTH)

AF:

0.299

AC:

630

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1756

3512

5269

7025

8781

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.342

Hom.:

41457

Bravo

AF:

0.332

Asia WGS

AF:

0.439

AC:

1529

AN:

3478

EpiCase

AF:

0.348

EpiControl

AF:

0.344

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.2

(source)

DANN

Benign

0.72

PhyloP100

-0.94

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000073

dbscSNV1_RF

Benign

0.012

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over