1-86560249-A-G

Variant names:

• chr1-86560249-A-G
• rs2231583
• NM_012128.4:c.339A>G

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_012128.4(CLCA4):​c.339A>G​(p.Arg113Arg) 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:3
• Conservation: PhyloP100: 0.123
• 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: Benign. The variant received -17 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 Benign/Likely_benign. ClinVar VariationId 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.
• BS2: High Homozygotes in GnomAdExome4 at 8 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.339A>G	p.Arg113Arg	synonymous	Exon 3 of 14	NP_036260.2	Q14CN2-1
	CLCA4	NR_024602.2		n.381A>G		non_coding_transcript_exon	Exon 3 of 13

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLCA4	ENST00000370563.3	TSL:1 MANE Select	c.339A>G	p.Arg113Arg	synonymous	Exon 3 of 14	ENSP00000359594.3	Q14CN2-1
	CLCA4	ENST00000862142.1		c.339A>G	p.Arg113Arg	synonymous	Exon 3 of 14	ENSP00000532201.1
	CLCA4	ENST00000862141.1		c.339A>G	p.Arg113Arg	synonymous	Exon 3 of 14	ENSP00000532200.1

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

GnomAD2 exomes AF: 0.00206 AC: 514 AN: 249294 AF XY: 0.00231

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 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

African (AFR) AF: 0.000478 AC: 16 AN: 33470

American (AMR) AF: 0.00107 AC: 48 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00101 AC: 87 AN: 86236

European-Finnish (FIN) AF: 0.000992 AC: 53 AN: 53416

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5768

European-Non Finnish (NFE) AF: 0.00250 AC: 2779 AN: 1111880

Other (OTH) AF: 0.00229 AC: 138 AN: 60388

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

African (AFR) AF: 0.000577 AC: 24 AN: 41576

American (AMR) AF: 0.000654 AC: 10 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68044

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00270 Hom.: 0

Bravo AF: 0.00163

EpiCase AF: 0.00425

EpiControl AF: 0.00403

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	10
DANN	Benign	0.66
PhyloP100		0.12
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs2231583; hg19: chr1-87025932;