Genetic Variant SCML2:p.Thr20Ser (chrX-18330619-G-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.59C>G(p.Thr20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000941 in 1,062,450 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T20I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.4e-7 ( 0 hom. 0 hem. )

Consequence

SCML2
NM_006089.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.113

Publications

0 publications found

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=0.03043887).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006089.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCML2	NM_006089.3	MANE Select	c.59C>G	p.Thr20Ser	missense	Exon 3 of 15	NP_006080.1	Q9UQR0-1
	SCML2	NR_033717.2		n.180C>G		non_coding_transcript_exon	Exon 3 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SCML2	ENST00000251900.9	TSL:1 MANE Select	c.59C>G	p.Thr20Ser	missense	Exon 3 of 15	ENSP00000251900.4	Q9UQR0-1
SCML2	ENST00000926833.1		c.59C>G	p.Thr20Ser	missense	Exon 3 of 15	ENSP00000596892.1
SCML2	ENST00000926834.1		c.59C>G	p.Thr20Ser	missense	Exon 4 of 16	ENSP00000596893.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.41e-7

AC:

AN:

1062450

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

334680

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000396

AC:

AN:

25256

American (AMR)

AF:

0.00

AC:

AN:

32405

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18669

East Asian (EAS)

AF:

0.00

AC:

AN:

29279

South Asian (SAS)

AF:

0.00

AC:

AN:

48786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40127

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4008

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819221

Other (OTH)

AF:

0.00

AC:

AN:

44699

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.33

(source)

DANN

Benign

0.29

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.30

M_CAP

Benign

0.0014

MetaRNN

Benign

0.030

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.63

PhyloP100

-0.11

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.32

REVEL

Benign

0.053

Sift

Benign

0.88

Sift4G

Benign

1.0

Polyphen

0.0020

Vest4

0.064

MutPred

0.19

Gain of relative solvent accessibility (P = 0.0999)

MVP

0.043

MPC

0.53

ClinPred

0.14

GERP RS

-0.080

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.028

gMVP

0.097

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over