Genetic Variant NM_012128.4:c.424A>C (chr1-86560334-A-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012128.4(CLCA4):c.424A>C(p.Lys142Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000222 in 1,613,822 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 2 hom. )

Consequence

CLCA4
NM_012128.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 3.51

Publications

4 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CLCA4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0077730417).

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012128.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCA4	NM_012128.4	MANE Select	c.424A>C	p.Lys142Gln	missense	Exon 3 of 14	NP_036260.2	Q14CN2-1
	CLCA4	NR_024602.2		n.466A>C		non_coding_transcript_exon	Exon 3 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCA4	ENST00000370563.3	TSL:1 MANE Select	c.424A>C	p.Lys142Gln	missense	Exon 3 of 14	ENSP00000359594.3	Q14CN2-1
CLCA4	ENST00000862142.1		c.424A>C	p.Lys142Gln	missense	Exon 3 of 14	ENSP00000532201.1
CLCA4	ENST00000862141.1		c.424A>C	p.Lys142Gln	missense	Exon 3 of 14	ENSP00000532200.1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000325

AC:

AN:

248912

AF XY:

0.000385

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00288

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000228

AC:

333

AN:

1461502

Hom.:

Cov.:

AF XY:

0.000264

AC XY:

192

AN XY:

727078

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33460

American (AMR)

AF:

0.000112

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00287

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.000928

AC:

AN:

86196

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00295

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.000103

AC:

115

AN:

1111836

Other (OTH)

AF:

0.000546

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000171

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.0000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000829

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000351

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.000306

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000356

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.045

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.38

M_CAP

Benign

0.0032

MetaRNN

Benign

0.0078

MetaSVM

Benign

-0.99

MutationAssessor

Pathogenic

3.2

PhyloP100

3.5

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.1

REVEL

Benign

0.068

Sift

Benign

0.14

Sift4G

Benign

0.36

Polyphen

0.078

Vest4

0.33

MVP

0.13

MPC

0.12

ClinPred

0.090

GERP RS

4.6

Varity_R

0.12

gMVP

0.37

Mutation Taster

=96/4

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over