Genetic Variant SLAIN2:p.Ala180Val (chr4-48377896-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_020846.2(SLAIN2):c.539C>T(p.Ala180Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,612,510 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000096 ( 0 hom. )

Consequence

SLAIN2
NM_020846.2 missense, splice_region

Scores

Splicing: ADA: 0.9944

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19

Variant links:

Genes affected

SLAIN2 (HGNC:29282): (SLAIN motif family member 2) Involved in cytoplasmic microtubule organization; microtubule nucleation; and positive regulation of microtubule polymerization. Located in centrosome and cytosol. Colocalizes with microtubule plus-end. [provided by Alliance of Genome Resources, Apr 2022]

SLAIN2 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SLAIN2	NM_020846.2 link	c.539C>T	p.Ala180Val	missense_variant, splice_region_variant	Exon 3 of 8	ENST00000264313.11	NP_065897.1	Q9P270A0A024R9T6
SLAIN2	XM_005248121.4 link	c.539C>T	p.Ala180Val	missense_variant, splice_region_variant	Exon 3 of 9		XP_005248178.1
SLAIN2	XM_047416023.1 link	c.116C>T	p.Ala39Val	missense_variant, splice_region_variant	Exon 3 of 9		XP_047271979.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLAIN2	ENST00000264313.11 link	c.539C>T	p.Ala180Val	missense_variant, splice_region_variant	Exon 3 of 8	1	NM_020846.2	ENSP00000264313.5	Q9P270
SLAIN2	ENST00000506375.1 link	n.150C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3	5
SLAIN2	ENST00000512093.5 link	c.-41C>T		upstream_gene_variant		5		ENSP00000425923.1	D6RIF6

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000928

AC:

AN:

247752

Hom.:

AF XY:

0.0000967

AC XY:

AN XY:

134438

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000558

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000959

AC:

140

AN:

1460316

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

726390

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000135

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000102

Gnomad4 OTH exome

AF:

0.0000663

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000193

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000745

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.539C>T (p.A180V) alteration is located in exon 3 (coding exon 3) of the SLAIN2 gene. This alteration results from a C to T substitution at nucleotide position 539, causing the alanine (A) at amino acid position 180 to be replaced by a valine (V). 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

0.078

BayesDel_addAF

Uncertain

0.032

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.084

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.0097

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.6

REVEL

Benign

0.18

Sift

Uncertain

0.0030

Sift4G

Benign

0.14

Polyphen

0.99

Vest4

0.31

MVP

0.30

MPC

0.21

ClinPred

0.27

GERP RS

5.5

Varity_R

0.20

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.92

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