8-36808788-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001031836.3(KCNU1):c.727C>T(p.His243Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KCNU1 NM_001031836.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.04

Genes affected

KCNU1 (HGNC:18867): (potassium calcium-activated channel subfamily U member 1) This gene encodes a member of the potassium channel family of proteins. The encoded voltage-gated ion channel allows the outward flow of potassium ions during plasma membrane hyperpolarization in sperm. Opening of this channel may be regulated by calcium ion levels. Homozygous knockout mice that lack the related mouse gene exhibit male sterility. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.887

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNU1	NM_001031836.3	c.727C>T	p.His243Tyr	missense_variant	7/27	ENST00000399881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNU1	ENST00000399881.8	c.727C>T	p.His243Tyr	missense_variant	7/27	2	NM_001031836.3	P1
KCNU1	ENST00000522372.5	c.727C>T	p.His243Tyr	missense_variant, NMD_transcript_variant	7/28	1
KCNU1	ENST00000523973.5	c.727C>T	p.His243Tyr	missense_variant	7/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Feb 03, 2022

The c.727C>T (p.H243Y) alteration is located in exon 7 (coding exon 7) of the KCNU1 gene. This alteration results from a C to T substitution at nucleotide position 727, causing the histidine (H) at amino acid position 243 to be replaced by a tyrosine (Y). 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	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Benign	0.016	T
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.068	T;D
Sift4G	Benign	0.20	T;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.77		Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);
MVP		0.55
MPC		0.19
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.80
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr8-36666306;