1-86571204-C-T

Position:

chr1-86571204-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_012128.4(CLCA4):c.1310C>T(p.Ala437Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,612,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A437G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

CLCA4
NM_012128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Variant links:

Genes affected

CLCA4 (HGNC:2018): (chloride channel accessory 4) The protein encoded by this gene belongs to the calcium sensitive chloride conductance protein family. To date, all members of this gene family map to the same site on chromosome 1p31-p22 and share high degrees of homology in size, sequence and predicted structure, but differ significantly in their tissue distributions. Alternative splicing results in multiple transcript variants, only one of which is thought to be protein coding. [provided by RefSeq, Dec 2008]

CLCA4 links:

CLCA4-AS1 (HGNC:):

CLCA4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCA4	NM_012128.4 linkuse as main transcript	c.1310C>T	p.Ala437Val	missense_variant	8/14	ENST00000370563.3	NP_036260.2	Q14CN2-1
CLCA4	XM_011541015.3 linkuse as main transcript	c.1157C>T	p.Ala386Val	missense_variant	8/14		XP_011539317.1
CLCA4	NR_024602.2 linkuse as main transcript	n.1243C>T		non_coding_transcript_exon_variant	7/13
CLCA4-AS1	NR_135837.1 linkuse as main transcript	n.1497G>A		non_coding_transcript_exon_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCA4	ENST00000370563.3 linkuse as main transcript	c.1310C>T	p.Ala437Val	missense_variant	8/14	1	NM_012128.4	ENSP00000359594.3	Q14CN2-1
CLCA4-AS1	ENST00000456587.1 linkuse as main transcript	n.499G>A		non_coding_transcript_exon_variant	4/4	3
CLCA4	ENST00000496322.1 linkuse as main transcript	n.89C>T		non_coding_transcript_exon_variant	1/2	3
CLCA4-AS1	ENST00000699483.1 linkuse as main transcript	n.1488G>A		non_coding_transcript_exon_variant	5/5

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151944

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

249066

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135112

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000871

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:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1460716

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726656

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000672

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:

0.0000180

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151944

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000827

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

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

Jul 26, 2024

The c.1310C>T (p.A437V) alteration is located in exon 8 (coding exon 8) of the CLCA4 gene. This alteration results from a C to T substitution at nucleotide position 1310, causing the alanine (A) at amino acid position 437 to be replaced by a valine (V). 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

Uncertain

0.47

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.039

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.16

MutationAssessor

Pathogenic

3.7

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.50

Sift

Benign

0.032

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.74

MutPred

0.89

Loss of sheet (P = 0.302);

MVP

0.68

MPC

0.34

ClinPred

0.98

GERP RS

5.3

Varity_R

0.30

gMVP

0.67

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