1-86560249-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_012128.4(CLCA4):c.339A>G(p.Arg113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,614,032 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (8 hom.)
• Consequence: CLCA4 NM_012128.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.123

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-86560249-A-G is Benign according to our data. Variant chr1-86560249-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 773148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.123 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLCA4	NM_012128.4	c.339A>G	p.Arg113=	synonymous_variant	3/14	ENST00000370563.3
CLCA4	XM_011541015.3	c.186A>G	p.Arg62=	synonymous_variant	3/14
CLCA4	NR_024602.2	n.381A>G		non_coding_transcript_exon_variant	3/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLCA4	ENST00000370563.3	c.339A>G	p.Arg113=	synonymous_variant	3/14	1	NM_012128.4	P1

Frequencies

GnomAD3 genomes AF: 0.00169 AC: 257 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00206 AC: 514 AN: 249294 Hom.: 1 AF XY: 0.00231 AC XY: 312 AN XY: 135248

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000986

Gnomad ASJ exome AF: 0.00566

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000785

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00303

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00226 AC: 3310 AN: 1461688 Hom.: 8 Cov.: 31 AF XY: 0.00227 AC XY: 1653 AN XY: 727152

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00482

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00101

Gnomad4 FIN exome AF: 0.000992

Gnomad4 NFE exome AF: 0.00250

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00169 AC: 257 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.00168 AC XY: 125 AN XY: 74494

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00266

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00163

EpiCase AF: 0.00425

EpiControl AF: 0.00403

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	CLCA4: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 05, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	10
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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

Other links and lift over

dbSNP: rs2231583; hg19: chr1-87025932;