Variant 6-109444204-CCT-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_022765.4(MICAL1):c.3189_3190del(p.Ala1065ProfsTer?) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,762 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

MICAL1
NM_022765.4 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.00900

Variant links:

Genes affected

MICAL1 (HGNC:20619): (microtubule associated monooxygenase, calponin and LIM domain containing 1) This gene encodes an enzyme that oxidizes methionine residues on actin, thereby promoting depolymerization of actin filaments. This protein interacts with and regulates signalling by NEDD9/CAS-L (neural precursor cell expressed, developmentally down-regulated 9). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

MICAL1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-109444204-CCT-C is Pathogenic according to our data. Variant chr6-109444204-CCT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2722147.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MICAL1	NM_022765.4 linkuse as main transcript	c.3189_3190del	p.Ala1065ProfsTer?	frameshift_variant	25/25	ENST00000358807.8	NP_073602.3
MICAL1	NM_001159291.2 linkuse as main transcript	c.2931_2932del	p.Ala979ProfsTer?	frameshift_variant	24/24		NP_001152763.1
MICAL1	NM_001286613.2 linkuse as main transcript	c.3246_3247del	p.Ala1084ProfsTer?	frameshift_variant	25/25		NP_001273542.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MICAL1	ENST00000358807.8 linkuse as main transcript	c.3189_3190del	p.Ala1065ProfsTer?	frameshift_variant	25/25	1	NM_022765.4	ENSP00000351664	P2	Q8TDZ2-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250528

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135690

show subpopulations

Gnomad AFR exome

AF:

0.0000620

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1460762

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

726692

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000895

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2023

This sequence change results in a frameshift in the MICAL1 gene (p.Ala1084Profs*?). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the MICAL1 protein and extend the protein by an uncertain number of additional amino acid residues. This variant is present in population databases (rs776954085, gnomAD 0.007%). This frameshift has been observed in individual(s) with autosomal dominant lateral temporal lobe epilepsy (PMID: 29394500). It has also been observed to segregate with disease in related individuals. This variant is also known as c.3189-3190del (p.Ala1065fs). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects MICAL1 function (PMID: 29394500). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over