rs1555528807

Variant names:

• chr10-77637609-TGCT-C
• rs1555528807
• NM_001161352.2:c.31_34delAGCAinsG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001161352.2(KCNMA1):​c.31_34delAGCAinsG​(p.Ser11_Ser12delinsGly) variant causes a missense, conservative inframe deletion change involving the alteration of a non-conserved nucleotide. 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: KCNMA1 NM_001161352.2 missense, conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 1.13

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the KCNMA1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 25 curated benign missense variants. Gene score misZ: 5.0622 (above the threshold of 3.09). Trascript score misZ: 6.5162 (above the threshold of 3.09). GenCC associations: The gene is linked to cerebellar atrophy, developmental delay, and seizures, generalized epilepsy-paroxysmal dyskinesia syndrome, Liang-Wang syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KCNMA1	NM_001161352.2	c.31_34delAGCAinsG	p.Ser11_Ser12delinsGly	missense_variant, conservative_inframe_deletion	Exon 1 of 28	ENST00000286628.14	NP_001154824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KCNMA1	ENST00000286628.14	c.31_34delAGCAinsG	p.Ser11_Ser12delinsGly	missense_variant, conservative_inframe_deletion	Exon 1 of 28	1	NM_001161352.2	ENSP00000286628.8

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Oct 12, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in several individuals in one family with atrial fibrillation and other cardiac arrhythmias (Pineda et al., 2021), but it has not been reported in association with neurodevelopmental disorders to our knowledge; In-frame deletion of 2 amino acids and insertion of 1 amino acid in a non-repeat region; In silico analysis supports that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33629867) -

Oct 03, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Jan 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: KCNMA1 c.31_34delinsG (p.Ser11_Ser12delinsGly) results in an in-frame deletion-insertion that is predicted to delete 1 amino acid from the protein and also cause changes in 1 amino acid. The variant was absent in 155796 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.31_34delinsG has been reported in the literature in at least one family affected with atrial fibrillation (Pineda_2021), however, these report(s) do not provide unequivocal conclusions about association of the variant with Paroxysmal Nonkinesigenic Dyskinesia, 3, With Or Without Generalized Epilepsy. One publication reports experimental evidence demonstrating that the variant may impact protein function in the cardiac conduction system, however, studies evaluating impact on neurological function have not been performed to our knowledge. The following publication have been ascertained in the context of this evaluation (PMID: 33629867). ClinVar contains an entry for this variant (Variation ID: 464297). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Sep 03, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.31_34delinsG, results in the deletion of 2 amino acids of the KCNMA1 protein and insertion of 1 amino acid (p.Ser11_Ser12delinsGly) but otherwise preserves the integrity of the reading frame. This variant is reported as two separate entries in the ExAC population database (c.34_36del, 0.03806% and c.31A>G, 0.02472%). However, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with KCNMA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 464297). Experimental studies and prediction algorithms are not available or were not evaluated for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cerebellar atrophy, developmental delay, and seizures;C5231421:Epilepsy, idiopathic generalized, susceptibility to, 16;C5231479:Liang-Wang syndrome;C5574945:Generalized epilepsy-paroxysmal dyskinesia syndrome Uncertain:1

Jan 18, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555528807; hg19: chr10-79397367;