Genetic Variant SCML2:p.Ile323Val (chrX-18260273-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_006089.3(SCML2):c.967A>G(p.Ile323Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000334 in 1,196,887 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000018 ( 0 hom. 0 hem. )

Consequence

SCML2
NM_006089.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -3.10

Variant links:

Genes affected

SCML2 (HGNC:10581): (Scm polycomb group protein like 2) This gene encodes a member of the Polycomb group proteins. These proteins form the Polycomb repressive complexes which are involved in transcriptional repression. The encoded protein binds histone peptides that are monomethylated at lysine residues and may be involved in regulating homeotic gene expression during development. [provided by RefSeq, Jun 2010]

SCML2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.014018059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCML2	NM_006089.3 link	c.967A>G	p.Ile323Val	missense_variant	Exon 9 of 15	ENST00000251900.9	NP_006080.1	Q9UQR0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCML2	ENST00000251900.9 link	c.967A>G	p.Ile323Val	missense_variant	Exon 9 of 15	1	NM_006089.3	ENSP00000251900.4		Q9UQR0-1
SCML2	ENST00000665583.1 link	c.175A>G	p.Ile59Val	missense_variant	Exon 3 of 8			ENSP00000499630.1		B4DRC2

Frequencies

GnomAD3 genomes

AF:

0.0000180

AC:

AN:

111305

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000560

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000575

AC:

AN:

173974

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000767

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000184

AC:

AN:

1085530

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

26063

Gnomad4 AMR exome

AF:

0.00

AC:

AN:

34127

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

19013

Gnomad4 EAS exome

AF:

0.0000333

AC:

AN:

29999

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

51185

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

40204

Gnomad4 NFE exome

AF:

0.00000120

AC:

AN:

835290

Gnomad4 Remaining exome

AF:

0.00

AC:

AN:

45579

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000180

AC:

AN:

111357

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33603

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.00

AC:

AN:

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.000562

AC:

0.00056164

AN:

0.00056164

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 20, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.967A>G (p.I323V) alteration is located in exon 9 (coding exon 8) of the SCML2 gene. This alteration results from a A to G substitution at nucleotide position 967, causing the isoleucine (I) at amino acid position 323 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

0.065

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-1.2

CADD

Benign

0.0050

DANN

Benign

0.23

DEOGEN2

Benign

0.019

FATHMM_MKL

Benign

0.0030

LIST_S2

Benign

0.49

M_CAP

Benign

0.0036

MetaRNN

Benign

0.014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.41

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.12

REVEL

Benign

0.025

Sift

Benign

0.69

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.020

MVP

0.043

MPC

0.49

ClinPred

0.025

GERP RS

-8.6

Varity_R

0.032

gMVP

0.13

Mutation Taster

=96/4

polymorphism

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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