Genetic Variant NM_006089.3:c.1444A>G (chrX-18256860-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006089.3(SCML2):c.1444A>G(p.Lys482Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000075 in 1,067,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000075 ( 0 hom. 2 hem. )

Consequence

SCML2
NM_006089.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.17

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05207455).

BS2

High Hemizygotes in GnomAdExome4 at 2 gene

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.1444A>G	p.Lys482Glu	missense	Exon 11 of 15	NP_006080.1
	SCML2	NR_033717.2		n.1565A>G		non_coding_transcript_exon	Exon 11 of 16

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SCML2	ENST00000251900.9	TSL:1 MANE Select	c.1444A>G	p.Lys482Glu	missense	Exon 11 of 15	ENSP00000251900.4
SCML2	ENST00000926833.1		c.1444A>G	p.Lys482Glu	missense	Exon 11 of 15	ENSP00000596892.1
SCML2	ENST00000926834.1		c.1444A>G	p.Lys482Glu	missense	Exon 12 of 16	ENSP00000596893.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000750

AC:

AN:

1067368

Hom.:

Cov.:

AF XY:

0.00000582

AC XY:

AN XY:

343656

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24755

American (AMR)

AF:

0.00

AC:

AN:

27853

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17817

East Asian (EAS)

AF:

0.00

AC:

AN:

29438

South Asian (SAS)

AF:

0.00

AC:

AN:

48394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39918

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3978

European-Non Finnish (NFE)

AF:

0.00000963

AC:

AN:

830487

Other (OTH)

AF:

0.00

AC:

AN:

44728

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.92

CADD

Benign

2.3

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.018

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.42

M_CAP

Benign

0.0080

MetaRNN

Benign

0.052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

1.2

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.39

REVEL

Benign

0.028

Sift

Benign

0.088

Sift4G

Benign

0.18

Polyphen

0.0020

Vest4

0.096

MutPred

0.27

Loss of ubiquitination at K482 (P = 9e-04)

MVP

0.15

MPC

0.86

ClinPred

0.059

GERP RS

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.072

gMVP

0.42

Mutation Taster

=80/20

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

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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