1-86563739-G-T

Variant names:

• chr1-86563739-G-T
• rs368121159
• NM_012128.4:c.527G>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>T​(p.Arg176Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,455,892 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R176H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CLCA4 NM_012128.4 missense
• Clinical Significance: Not reported in ClinVar
• 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>T	p.Arg176Leu	missense	Exon 4 of 14	NP_036260.2	Q14CN2-1
	CLCA4	NR_024602.2		n.491-1535G>T		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>T	p.Arg176Leu	missense	Exon 4 of 14	ENSP00000359594.3	Q14CN2-1
	CLCA4	ENST00000862142.1		c.527G>T	p.Arg176Leu	missense	Exon 4 of 14	ENSP00000532201.1
	CLCA4	ENST00000862141.1		c.527G>T	p.Arg176Leu	missense	Exon 4 of 14	ENSP00000532200.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245962 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.00000412 AC: 6 AN: 1455892 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724322

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

American (AMR) AF: 0.0000681 AC: 3 AN: 44060

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39456

South Asian (SAS) AF: 0.00 AC: 0 AN: 85302

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108406

Other (OTH) AF: 0.00 AC: 0 AN: 60174

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.18
DANN	Benign	0.52
DEOGEN2	Benign	0.023	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.057	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.32
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.018
Sift	Benign	0.78	T
Sift4G	Benign	0.67	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.51		Loss of MoRF binding (P = 0.0207)
MVP		0.081
MPC		0.082
ClinPred		0.044	T
GERP RS		-7.9
Varity_R		0.048
gMVP		0.48
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.28		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;