X-18258073-G-C

Variant names:

• chrX-18258073-G-C
• rs779557253
• NM_006089.3:c.1244C>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.1244C>G​(p.Pro415Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,208,030 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 21)
  • Exomes 𝑓: 0.000024 (0 hom. 7 hem.)
• Consequence: SCML2 NM_006089.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.73

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=0.018807739).
• BS2: High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCML2	NM_006089.3	c.1244C>G	p.Pro415Arg	missense_variant	Exon 10 of 15	ENST00000251900.9	NP_006080.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCML2	ENST00000251900.9	c.1244C>G	p.Pro415Arg	missense_variant	Exon 10 of 15	1	NM_006089.3	ENSP00000251900.4
SCML2	ENST00000665583.1	c.452C>G	p.Pro151Arg	missense_variant	Exon 4 of 8			ENSP00000499630.1

Frequencies

GnomAD3 genomes AF: 0.0000451 AC: 5 AN: 110807 Hom.: 0 Cov.: 21

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00143

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: 0.0000709 AC: 13 AN: 183446 AF XY: 0.0000442

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000938

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000237 AC: 26 AN: 1097177 Hom.: 0 Cov.: 30 AF XY: 0.0000193 AC XY: 7 AN XY: 362551

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26381

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 35202

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19378

Gnomad4 EAS exome AF: 0.000762 AC: 23 AN: 30201

Gnomad4 SAS exome AF: 0.0000185 AC: 1 AN: 54124

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40528

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 841169

Gnomad4 Remaining exome AF: 0.0000434 AC: 2 AN: 46058

GnomAD4 genome AF: 0.0000451 AC: 5 AN: 110853 Hom.: 0 Cov.: 21 AF XY: 0.0000303 AC XY: 1 AN XY: 33049

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00144 AC: 0.00143678 AN: 0.00143678

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1244C>G (p.P415R) alteration is located in exon 10 (coding exon 9) of the SCML2 gene. This alteration results from a C to G substitution at nucleotide position 1244, causing the proline (P) at amino acid position 415 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	0.28
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.044	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.019	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.055
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.014	D
Polyphen		0.10	B
Vest4		0.26
MutPred		0.30		Loss of loop (P = 0.0374);
MVP		0.26
MPC		1.2
ClinPred		0.18	T
GERP RS		4.5
Varity_R		0.29
gMVP		0.30
Mutation Taster		=100/0	polymorphism

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: rs779557253; hg19: chrX-18276193;