Variant 1-86560071-A-G 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.299A>G(p.His100Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000943 in 1,580,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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: 0.000098 ( 0 hom. )

Consequence

CLCA4
NM_012128.4 missense, splice_region

Scores

Splicing: ADA: 0.07960

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.07

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21030128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLCA4	NM_012128.4 linkuse as main transcript	c.299A>G	p.His100Arg	missense_variant, splice_region_variant	2/14	ENST00000370563.3	NP_036260.2	Q14CN2-1
CLCA4	XM_011541015.3 linkuse as main transcript	c.146A>G	p.His49Arg	missense_variant, splice_region_variant	2/14		XP_011539317.1
CLCA4	NR_024602.2 linkuse as main transcript	n.341A>G		splice_region_variant, non_coding_transcript_exon_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLCA4	ENST00000370563.3 linkuse as main transcript	c.299A>G	p.His100Arg	missense_variant, splice_region_variant	2/14	1	NM_012128.4	ENSP00000359594.3		Q14CN2-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000409

AC:

AN:

220010

Hom.:

AF XY:

0.0000417

AC XY:

AN XY:

119912

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000858

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000980

AC:

140

AN:

1428354

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

709356

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000126

Gnomad4 OTH exome

AF:

0.0000170

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000109

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000331

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

Sep 11, 2024

The c.299A>G (p.H100R) alteration is located in exon 2 (coding exon 2) of the CLCA4 gene. This alteration results from a A to G substitution at nucleotide position 299, causing the histidine (H) at amino acid position 100 to be replaced by an arginine (R). 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

-0.40

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.024

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

M_CAP

Benign

0.0033

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.61

REVEL

Benign

0.059

Sift

Benign

0.036

Sift4G

Benign

0.17

Polyphen

0.43

Vest4

0.27

MVP

0.17

MPC

0.096

ClinPred

0.13

GERP RS

3.1

Varity_R

0.073

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.080

dbscSNV1_RF

Benign

0.25

SpliceAI score (max)

0.040

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