Genetic Variant CLCA1:p.Thr812Thr (chr1-86499736-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_001285.4(CLCA1):c.2436T>C(p.Thr812Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,607,498 control chromosomes in the GnomAD database, including 64,776 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.28 ( 6061 hom., cov: 33)

Exomes 𝑓: 0.28 ( 58715 hom. )

Consequence

CLCA1
NM_001285.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.929

Publications

20 publications found

Variant links:

Genes affected

CLCA1 (HGNC:2015): (chloride channel accessory 1) This gene encodes a member of the calcium sensitive chloride conductance protein family. To date, all members of this gene family map to the same region on chromosome 1p31-p22 and share a high degree of homology in size, sequence, and predicted structure, but differ significantly in their tissue distributions. The encoded protein is expressed as a precursor protein that is processed into two cell-surface-associated subunits, although the site at which the precursor is cleaved has not been precisely determined. The encoded protein may be involved in mediating calcium-activated chloride conductance in the intestine. [provided by RefSeq, Jul 2008]

CLCA1 links:

ENSG00000299069 (HGNC:):

ENSG00000299069 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP7

Synonymous conserved (PhyloP=-0.929 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLCA1	NM_001285.4 link	c.2436T>C	p.Thr812Thr	synonymous_variant	Exon 14 of 14	ENST00000394711.2	NP_001276.3	A8K7I4
LOC124904210	XR_007066206.1 link	n.226-18928A>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CLCA1	ENST00000394711.2 link	c.2436T>C	p.Thr812Thr	synonymous_variant	Exon 14 of 14	1	NM_001285.4	ENSP00000378200.1	A8K7I4
CLCA1	ENST00000234701.7 link	c.2436T>C	p.Thr812Thr	synonymous_variant	Exon 15 of 15	1		ENSP00000234701.3	A8K7I4
ENSG00000299069	ENST00000760295.1 link	n.187-902A>G		intron_variant	Intron 2 of 4

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41897

AN:

152074

Hom.:

6061

Cov.:

show subpopulations

Gnomad AFR

AF:

0.269

Gnomad AMI

AF:

0.294

Gnomad AMR

AF:

0.240

Gnomad ASJ

AF:

0.237

Gnomad EAS

AF:

0.531

Gnomad SAS

AF:

0.407

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.268

GnomAD2 exomes

AF:

0.297

AC:

74506

AN:

250978

AF XY:

0.300

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.261

Gnomad ASJ exome

AF:

0.240

Gnomad EAS exome

AF:

0.553

Gnomad FIN exome

AF:

0.248

Gnomad NFE exome

AF:

0.260

Gnomad OTH exome

AF:

0.272

GnomAD4 exome

AF:

0.277

AC:

403592

AN:

1455306

Hom.:

58715

Cov.:

AF XY:

0.280

AC XY:

203152

AN XY:

724342

show subpopulations

African (AFR)

AF:

0.269

AC:

8972

AN:

33318

American (AMR)

AF:

0.259

AC:

11576

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.242

AC:

6318

AN:

26098

East Asian (EAS)

AF:

0.510

AC:

20208

AN:

39650

South Asian (SAS)

AF:

0.398

AC:

34238

AN:

86118

European-Finnish (FIN)

AF:

0.251

AC:

13397

AN:

53270

Middle Eastern (MID)

AF:

0.214

AC:

1235

AN:

5762

European-Non Finnish (NFE)

AF:

0.262

AC:

290323

AN:

1106180

Other (OTH)

AF:

0.288

AC:

17325

AN:

60192

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

15301

30603

45904

61206

76507

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9928

19856

29784

39712

49640

<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:

0.275

AC:

41917

AN:

152192

Hom.:

6061

Cov.:

AF XY:

0.280

AC XY:

20816

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.269

AC:

11152

AN:

41508

American (AMR)

AF:

0.240

AC:

3665

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.237

AC:

824

AN:

3472

East Asian (EAS)

AF:

0.531

AC:

2743

AN:

5170

South Asian (SAS)

AF:

0.406

AC:

1960

AN:

4828

European-Finnish (FIN)

AF:

0.242

AC:

2565

AN:

10594

Middle Eastern (MID)

AF:

0.214

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.266

AC:

18118

AN:

68002

Other (OTH)

AF:

0.265

AC:

559

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1558

3116

4674

6232

7790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

438

876

1314

1752

2190

<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:

0.267

Hom.:

17075

Bravo

AF:

0.273

Asia WGS

AF:

0.460

AC:

1602

AN:

3478

EpiCase

AF:

0.256

EpiControl

AF:

0.252

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.2

(source)

DANN

Benign

0.62

PhyloP100

-0.93

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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