1-214318137-C-T

Position:

• chr1-214318137-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020197.3(SMYD2):​c.407C>T​(p.Ser136Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMYD2 NM_020197.3 missense, splice_region
• Scores: Splicing: ADA: 0.9976
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.97

Genes affected

SMYD2 (HGNC:20982): (SET and MYND domain containing 2) SET domain-containing proteins, such as SMYD2, catalyze lysine methylation (Brown et al., 2006 [PubMed 16805913]).[supplied by OMIM, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMYD2	NM_020197.3	c.407C>T	p.Ser136Leu	missense_variant, splice_region_variant	4/12	ENST00000366957.10
SMYD2	XM_047425700.1	c.155C>T	p.Ser52Leu	missense_variant, splice_region_variant	3/11
SMYD2	XM_047425702.1	c.407C>T	p.Ser136Leu	missense_variant, splice_region_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMYD2	ENST00000366957.10	c.407C>T	p.Ser136Leu	missense_variant, splice_region_variant	4/12	1	NM_020197.3	P1
SMYD2	ENST00000460580.5	n.376C>T		splice_region_variant, non_coding_transcript_exon_variant	3/11	1
SMYD2	ENST00000471645.5	n.537C>T		splice_region_variant, non_coding_transcript_exon_variant	4/10	1
SMYD2	ENST00000491455.5	n.560C>T		splice_region_variant, non_coding_transcript_exon_variant	4/11	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2024

The c.407C>T (p.S136L) alteration is located in exon 4 (coding exon 4) of the SMYD2 gene. This alteration results from a C to T substitution at nucleotide position 407, causing the serine (S) at amino acid position 136 to be replaced by a leucine (L). 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	Uncertain	0.55
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.28
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.46		Loss of disorder (P = 0.0149);
MVP		0.57
MPC		0.91
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.11		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: rs1453127256; hg19: chr1-214491480; COSMIC: COSV65290438;