10-77110248-G-A

Position:

• chr10-77110248-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001161352.2(KCNMA1):​c.1056C>T​(p.Thr352=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00053 in 1,613,862 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00045 (4 hom.)
• Consequence: KCNMA1 NM_001161352.2 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.23

Genes affected

KCNMA1 (HGNC:6284): (potassium calcium-activated channel subfamily M alpha 1) This gene encodes the alpha subunit of calcium-activated BK channel. The encoded protein is involved in several physiological processes including smooth muscle contraction, neurotransmitter release and neuronal excitability. Mutations in this gene are associated with a spectrum of neurological disorders including Paroxysmal Nonkinesigenic Dyskinesia 3, Idiopathic Generalized Epilepsy 16 and Liang-Wang syndrome. [provided by RefSeq, Aug 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 10-77110248-G-A is Benign according to our data. Variant chr10-77110248-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 464291.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00135 (205/152222) while in subpopulation AMR AF= 0.0123 (188/15294). AF 95% confidence interval is 0.0109. There are 1 homozygotes in gnomad4. There are 114 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KCNMA1	NM_001161352.2	c.1056C>T	p.Thr352=	synonymous_variant	8/28	ENST00000286628.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KCNMA1	ENST00000286628.14	c.1056C>T	p.Thr352=	synonymous_variant	8/28	1	NM_001161352.2	A2

Frequencies

GnomAD3 genomes AF: 0.00134 AC: 204 AN: 152104 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00170 AC: 427 AN: 251486 Hom.: 2 AF XY: 0.00128 AC XY: 174 AN XY: 135916

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000445 AC: 651 AN: 1461640 Hom.: 4 Cov.: 32 AF XY: 0.000384 AC XY: 279 AN XY: 727134

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0117

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152222 Hom.: 1 Cov.: 33 AF XY: 0.00153 AC XY: 114 AN XY: 74422

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.0123

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000293 Hom.: 1

Bravo AF: 0.00174

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 24, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	2.3
DANN	Benign	0.60

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

Publications

LitVar

Other links and lift over

dbSNP: rs75207686; hg19: chr10-78870006;