X-18256934-T-C

Variant names:

• chrX-18256934-T-C
• rs201570126
• NM_006089.3:c.1370A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006089.3(SCML2):​c.1370A>G​(p.Gln457Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,206,708 control chromosomes in the GnomAD database, including 2 homozygotes. There are 111 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00038 (1 hom., 11 hem., cov: 23)
  • Exomes 𝑓: 0.00029 (1 hom. 100 hem.)
• Consequence: SCML2 NM_006089.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.88

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0100007355).
• BS2: High Hemizygotes in GnomAd4 at 11 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCML2	NM_006089.3	c.1370A>G	p.Gln457Arg	missense_variant	Exon 11 of 15	ENST00000251900.9	NP_006080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCML2	ENST00000251900.9	c.1370A>G	p.Gln457Arg	missense_variant	Exon 11 of 15	1	NM_006089.3	ENSP00000251900.4
SCML2	ENST00000665583.1	c.578A>G	p.Gln193Arg	missense_variant	Exon 5 of 8			ENSP00000499630.1

Frequencies

GnomAD3 genomes AF: 0.000384 AC: 43 AN: 111896 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00978

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00420

Gnomad NFE AF: 0.000225

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.000458 AC: 82 AN: 179020 AF XY: 0.000675

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00137

GnomAD4 exome AF: 0.000293 AC: 321 AN: 1094761 Hom.: 1 Cov.: 28 AF XY: 0.000278 AC XY: 100 AN XY: 360341

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26285

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 34947

Gnomad4 ASJ exome AF: 0.00983 AC: 190 AN: 19332

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30083

Gnomad4 SAS exome AF: 0.000149 AC: 8 AN: 53712

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40505

Gnomad4 NFE exome AF: 0.0000929 AC: 78 AN: 839821

Gnomad4 Remaining exome AF: 0.000675 AC: 31 AN: 45954

GnomAD4 genome AF: 0.000384 AC: 43 AN: 111947 Hom.: 1 Cov.: 23 AF XY: 0.000322 AC XY: 11 AN XY: 34123

Gnomad4 AFR AF: 0.0000324 AC: 0.0000324433 AN: 0.0000324433

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00978 AC: 0.00977811 AN: 0.00977811

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000225 AC: 0.000225479 AN: 0.000225479

Gnomad4 OTH AF: 0.00197 AC: 0.0019698 AN: 0.0019698

Alfa AF: 0.000672 Hom.: 34

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000412 AC: 50

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1370A>G (p.Q457R) alteration is located in exon 11 (coding exon 10) of the SCML2 gene. This alteration results from a A to G substitution at nucleotide position 1370, causing the glutamine (Q) at amino acid position 457 to be replaced by an arginine (R). 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	0.12
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	19
DANN	Benign	0.77
DEOGEN2	Benign	0.029	T
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Sift4G	Benign	0.58	T
Polyphen		0.33	B
Vest4		0.065
MVP		0.57
MPC		0.97
ClinPred		0.10	T
GERP RS		5.5
Varity_R		0.21
gMVP		0.65
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

dbSNP: rs201570126; hg19: chrX-18275054;