Variant 1-86565904-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012128.4(CLCA4):c.838G>A(p.Glu280Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,612,592 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

CLCA4
NM_012128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.872

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.113245636).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CLCA4	NM_012128.4 linkuse as main transcript	c.838G>A	p.Glu280Lys	missense_variant	6/14	ENST00000370563.3
CLCA4	XM_011541015.3 linkuse as main transcript	c.685G>A	p.Glu229Lys	missense_variant	6/14
CLCA4	NR_024602.2 linkuse as main transcript	n.771G>A		non_coding_transcript_exon_variant	5/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCA4	ENST00000370563.3 linkuse as main transcript	c.838G>A	p.Glu280Lys	missense_variant	6/14	1	NM_012128.4	P1	Q14CN2-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00236

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:

0.0000736

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000124

AC:

AN:

249110

Hom.:

AF XY:

0.000104

AC XY:

AN XY:

135158

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.000406

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:

0.000133

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000129

AC:

188

AN:

1460560

Hom.:

Cov.:

AF XY:

0.000114

AC XY:

AN XY:

726616

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000155

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000289

AC:

AN:

152032

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00236

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000736

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000269

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000910

AC:

EpiCase

AF:

0.0000548

EpiControl

AF:

0.000119

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.838G>A (p.E280K) alteration is located in exon 6 (coding exon 6) of the CLCA4 gene. This alteration results from a G to A substitution at nucleotide position 838, causing the glutamic acid (E) at amino acid position 280 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

Benign

0.079

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.47

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.058

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.80

M_CAP

Benign

0.0039

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.8

REVEL

Benign

0.15

Sift

Benign

0.27

Sift4G

Benign

0.39

Polyphen

0.75

Vest4

0.17

MVP

0.18

MPC

0.10

ClinPred

0.10

GERP RS

5.2

Varity_R

0.081

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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