Variant 1-86574543-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_012128.4(CLCA4):c.1471G>A(p.Glu491Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000323 in 1,610,384 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.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CLCA4
NM_012128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.30

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 (HGNC:):

CLCA4 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.769

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCA4	NM_012128.4 linkuse as main transcript	c.1471G>A	p.Glu491Lys	missense_variant	10/14	ENST00000370563.3	NP_036260.2	Q14CN2-1
CLCA4	XM_011541015.3 linkuse as main transcript	c.1318G>A	p.Glu440Lys	missense_variant	10/14		XP_011539317.1
CLCA4	NR_024602.2 linkuse as main transcript	n.1404G>A		non_coding_transcript_exon_variant	9/13
CLCA4-AS1	NR_135837.1 linkuse as main transcript	n.1293-3135C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CLCA4	ENST00000370563.3 linkuse as main transcript	c.1471G>A	p.Glu491Lys	missense_variant	10/14	1	NM_012128.4	ENSP00000359594.3	Q14CN2-1
CLCA4-AS1	ENST00000456587.1 linkuse as main transcript	n.295-3135C>T		intron_variant		3
CLCA4-AS1	ENST00000650379.1 linkuse as main transcript	n.2258-3135C>T		intron_variant
CLCA4-AS1	ENST00000699483.1 linkuse as main transcript	n.1284-3135C>T		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

151968

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000282

AC:

AN:

247994

Hom.:

AF XY:

0.0000371

AC XY:

AN XY:

134612

show subpopulations

Gnomad AFR exome

AF:

0.0000651

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000891

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1458298

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

725658

show subpopulations

Gnomad4 AFR exome

AF:

0.000180

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000189

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.0000672

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000331

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

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

Oct 24, 2024

The c.1471G>A (p.E491K) alteration is located in exon 10 (coding exon 10) of the CLCA4 gene. This alteration results from a G to A substitution at nucleotide position 1471, causing the glutamic acid (E) at amino acid position 491 to be replaced by a lysine (K). 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

0.38

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.034

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.57

MutationAssessor

Pathogenic

3.6

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.8

REVEL

Uncertain

0.40

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.67

MVP

0.70

MPC

0.43

ClinPred

0.99

GERP RS

5.9

Varity_R

0.70

gMVP

0.66

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

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