11-77622619-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001293.3(CLNS1A):c.527A>T(p.His176Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLNS1A NM_001293.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

Genes affected

CLNS1A (HGNC:2080): (chloride nucleotide-sensitive channel 1A) This gene encodes a protein that functions in multiple regulatory pathways. The encoded protein complexes with numerous cytosolic proteins and performs diverse functions including regulation of small nuclear ribonucleoprotein biosynthesis, platelet activation and cytoskeletal organization. The protein is also found associated with the plasma membrane where it functions as a chloride current regulator. Pseudogenes of this gene are found on chromosomes 1, 4 and 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLNS1A	NM_001293.3	c.527A>T	p.His176Leu	missense_variant	5/7	ENST00000525428.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLNS1A	ENST00000525428.6	c.527A>T	p.His176Leu	missense_variant	5/7	1	NM_001293.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.527A>T (p.H176L) alteration is located in exon 5 (coding exon 5) of the CLNS1A gene. This alteration results from a A to T substitution at nucleotide position 527, causing the histidine (H) at amino acid position 176 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	25
Dann	Benign	0.96
DEOGEN2	Uncertain	0.49	T;T;.;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	1.2	L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.013	D;D;T;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.70	P;.;P;P
Vest4		0.44
MutPred		0.41		Loss of catalytic residue at H176 (P = 0.0486);.;.;Loss of catalytic residue at H176 (P = 0.0486);
MVP		0.99
MPC		0.87
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-77333664;