Genetic Variant CLCA4:p.Asp39His (chr1-86547234-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_012128.4(CLCA4):c.115G>C(p.Asp39His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000865 in 1,607,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000091 ( 0 hom. )

Consequence

CLCA4
NM_012128.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.113

Publications

0 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09619516).

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.115G>C	p.Asp39His	missense	Exon 1 of 14	NP_036260.2	Q14CN2-1
	CLCA4	NR_024602.2		n.157G>C		non_coding_transcript_exon	Exon 1 of 13

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLCA4	ENST00000370563.3	TSL:1 MANE Select	c.115G>C	p.Asp39His	missense	Exon 1 of 14	ENSP00000359594.3	Q14CN2-1
CLCA4	ENST00000862142.1		c.115G>C	p.Asp39His	missense	Exon 1 of 14	ENSP00000532201.1
CLCA4	ENST00000862141.1		c.115G>C	p.Asp39His	missense	Exon 1 of 14	ENSP00000532200.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000451

AC:

AN:

243860

AF XY:

0.0000378

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000984

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000907

AC:

132

AN:

1454882

Hom.:

Cov.:

AF XY:

0.000101

AC XY:

AN XY:

723418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33204

American (AMR)

AF:

0.00

AC:

AN:

43332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25990

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.00

AC:

AN:

84116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53334

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000117

AC:

130

AN:

1109656

Other (OTH)

AF:

0.0000333

AC:

AN:

60140

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.436

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:

0.0000460

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41426

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000901

Hom.:

Bravo

AF:

0.000106

ESP6500AA

AF:

0.000273

AC:

ESP6500EA

AF:

0.000123

AC:

ExAC

AF:

0.0000662

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.060

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.82

M_CAP

Benign

0.0061

MetaRNN

Benign

0.096

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

PhyloP100

0.11

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.091

Sift

Benign

0.17

Sift4G

Benign

0.22

Polyphen

0.38

Vest4

0.16

MVP

0.32

MPC

0.20

ClinPred

0.096

GERP RS

-1.6

PromoterAI

0.0028

Neutral

(source)

Varity_R

0.058

gMVP

0.85

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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