1-86560311-C-T

Variant names:

• chr1-86560311-C-T
• rs200309705
• NM_012128.4:c.401C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_012128.4(CLCA4):​c.401C>T​(p.Thr134Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CLCA4 NM_012128.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.62
• 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.764

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.401C>T	p.Thr134Ile	missense	Exon 3 of 14	NP_036260.2	Q14CN2-1
	CLCA4	NR_024602.2		n.443C>T		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.401C>T	p.Thr134Ile	missense	Exon 3 of 14	ENSP00000359594.3	Q14CN2-1
	CLCA4	ENST00000862142.1		c.401C>T	p.Thr134Ile	missense	Exon 3 of 14	ENSP00000532201.1
	CLCA4	ENST00000862141.1		c.401C>T	p.Thr134Ile	missense	Exon 3 of 14	ENSP00000532200.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000116 AC: 29 AN: 249372 AF XY: 0.0000739

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000108 AC: 158 AN: 1461756 Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80 AN XY: 727186

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000122 AC: 136 AN: 1111902

Other (OTH) AF: 0.000132 AC: 8 AN: 60394

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74314

African (AFR) AF: 0.0000966 AC: 4 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000126 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000268 AC: 1

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

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	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.025	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.6
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.54
MVP		0.58
MPC		0.41
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.79
gMVP		0.84
Mutation Taster		=33/67	disease causing

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

Other links and lift over

dbSNP: rs200309705; hg19: chr1-87025994;