rs368121159

Variant names:

• chr1-86563739-G-A
• rs368121159
• NM_012128.4:c.527G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-86563739-G-A
• chr1-86563739-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_012128.4(CLCA4):​c.527G>A​(p.Arg176His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,607,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: CLCA4 NM_012128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.323
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.527G>A	p.Arg176His	missense	Exon 4 of 14	NP_036260.2	Q14CN2-1
	CLCA4	NR_024602.2		n.491-1535G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCA4	ENST00000370563.3	TSL:1 MANE Select	c.527G>A	p.Arg176His	missense	Exon 4 of 14	ENSP00000359594.3	Q14CN2-1
	CLCA4	ENST00000862142.1		c.527G>A	p.Arg176His	missense	Exon 4 of 14	ENSP00000532201.1
	CLCA4	ENST00000862141.1		c.527G>A	p.Arg176His	missense	Exon 4 of 14	ENSP00000532200.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000203 AC: 5 AN: 245962 AF XY: 0.0000299

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: 0.0000446

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000165 AC: 24 AN: 1455890 Hom.: 0 Cov.: 29 AF XY: 0.0000138 AC XY: 10 AN XY: 724322

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.00 AC: 0 AN: 44060

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39456

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85302

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1108404

Other (OTH) AF: 0.0000332 AC: 2 AN: 60174

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74352

African (AFR) AF: 0.0000723 AC: 3 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000227

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.00

EpiControl AF: 0.000180

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.2
DANN	Benign	0.91
DEOGEN2	Benign	0.040	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.062	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L
PhyloP100		-0.32
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.023
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.0010	B
Vest4		0.14
MVP		0.040
MPC		0.082
ClinPred		0.040	T
GERP RS		-7.9
Varity_R		0.028
gMVP		0.35
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: 30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368121159; hg19: chr1-87029422; COSMIC: COSV99760330;