Variant 1-86572667-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012128.4(CLCA4):c.1414G>A(p.Ala472Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,609,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00064 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

CLCA4
NM_012128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.31

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.044285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCA4	NM_012128.4 linkuse as main transcript	c.1414G>A	p.Ala472Thr	missense_variant	9/14	ENST00000370563.3	NP_036260.2	Q14CN2-1
CLCA4	XM_011541015.3 linkuse as main transcript	c.1261G>A	p.Ala421Thr	missense_variant	9/14		XP_011539317.1
CLCA4	NR_024602.2 linkuse as main transcript	n.1347G>A		non_coding_transcript_exon_variant	8/13
CLCA4-AS1	NR_135837.1 linkuse as main transcript	n.1293-1259C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCA4	ENST00000370563.3 linkuse as main transcript	c.1414G>A	p.Ala472Thr	missense_variant	9/14	1	NM_012128.4	ENSP00000359594.3		Q14CN2-1

Frequencies

GnomAD3 genomes

AF:

0.000645

AC:

AN:

151950

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00234

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000140

AC:

AN:

249702

Hom.:

AF XY:

0.000118

AC XY:

AN XY:

135330

show subpopulations

Gnomad AFR exome

AF:

0.00224

Gnomad AMR exome

AF:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000453

AC:

AN:

1457728

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

725388

show subpopulations

Gnomad4 AFR exome

AF:

0.00165

Gnomad4 AMR exome

AF:

0.0000448

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:

9.02e-7

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.000644

AC:

AN:

152068

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00234

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.000767

ESP6500AA

AF:

0.00206

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000181

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

Nov 08, 2022

The c.1414G>A (p.A472T) alteration is located in exon 9 (coding exon 9) of the CLCA4 gene. This alteration results from a G to A substitution at nucleotide position 1414, causing the alanine (A) at amino acid position 472 to be replaced by a threonine (T). 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

0.13

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.91

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.044

MetaSVM

Uncertain

0.15

MutationAssessor

Uncertain

2.9

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-3.5

REVEL

Uncertain

0.44

Sift

Uncertain

0.018

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.50

MVP

0.80

MPC

0.30

ClinPred

0.24

GERP RS

5.0

Varity_R

0.37

gMVP

0.57

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