X-18324029-T-A

Variant names:

• chrX-18324029-T-A
• rs766427319
• NM_006089.3:c.227A>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006089.3(SCML2):​c.227A>T​(p.Asn76Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,874 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic 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. N76S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: SCML2 NM_006089.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.76
• Publications: 0 publications found

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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

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.227A>T	p.Asn76Ile	missense	Exon 5 of 15	NP_006080.1	Q9UQR0-1
	SCML2	NR_033717.2		n.348A>T		non_coding_transcript_exon	Exon 5 of 16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCML2	ENST00000251900.9	TSL:1 MANE Select	c.227A>T	p.Asn76Ile	missense	Exon 5 of 15	ENSP00000251900.4	Q9UQR0-1
	SCML2	ENST00000926833.1		c.227A>T	p.Asn76Ile	missense	Exon 5 of 15	ENSP00000596892.1
	SCML2	ENST00000926834.1		c.227A>T	p.Asn76Ile	missense	Exon 6 of 16	ENSP00000596893.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097874 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 1 AN XY: 363232

African (AFR) AF: 0.00 AC: 0 AN: 26390

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30203

South Asian (SAS) AF: 0.00 AC: 0 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841799

Other (OTH) AF: 0.00 AC: 0 AN: 46087

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.8
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-8.8	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.67		Loss of disorder (P = 0.0926)
MVP		0.88
MPC		1.7
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.95
gMVP		0.95
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766427319; hg19: chrX-18342149;