rs2229716

Variant names:

• chr12-57232799-G-A
• rs2229716
• NM_005412.6:c.813G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The ENST00000328923.8(SHMT2):​c.813G>A​(p.Ala271Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,613,500 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.029 (83 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1127 hom.)
• Consequence: SHMT2 ENST00000328923.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.98
• Publications: 13 publications found

Genes affected

SHMT2 (HGNC:10852): (serine hydroxymethyltransferase 2) This gene encodes the mitochondrial form of a pyridoxal phosphate-dependent enzyme that catalyzes the reversible reaction of serine and tetrahydrofolate to glycine and 5,10-methylene tetrahydrofolate. The encoded product is primarily responsible for glycine synthesis. The activity of the encoded protein has been suggested to be the primary source of intracellular glycine. The gene which encodes the cytosolic form of this enzyme is located on chromosome 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

SHMT2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with cardiomyopathy, spasticity, and brain abnormalities

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.084).
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0704 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000328923.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT2	NM_005412.6	MANE Select	c.813G>A	p.Ala271Ala	synonymous	Exon 7 of 12	NP_005403.2
	SHMT2	NM_001166356.2		c.783G>A	p.Ala261Ala	synonymous	Exon 7 of 12	NP_001159828.1
	SHMT2	NM_001166357.1		c.750G>A	p.Ala250Ala	synonymous	Exon 7 of 12	NP_001159829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHMT2	ENST00000328923.8	TSL:1 MANE Select	c.813G>A	p.Ala271Ala	synonymous	Exon 7 of 12	ENSP00000333667.3
	SHMT2	ENST00000557487.5	TSL:1	c.783G>A	p.Ala261Ala	synonymous	Exon 7 of 12	ENSP00000452315.1
	SHMT2	ENST00000414700.7	TSL:1	c.750G>A	p.Ala250Ala	synonymous	Exon 7 of 12	ENSP00000406881.3

Frequencies

GnomAD3 genomes AF: 0.0287 AC: 4365 AN: 152234 Hom.: 83 Cov.: 33

Gnomad AFR AF: 0.00685

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0322

Gnomad ASJ AF: 0.0308

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0329

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0415

GnomAD2 exomes AF: 0.0296 AC: 7447 AN: 251246 AF XY: 0.0296

Gnomad AFR exome AF: 0.00720

Gnomad AMR exome AF: 0.0221

Gnomad ASJ exome AF: 0.0314

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0427

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0369 AC: 53852 AN: 1461148 Hom.: 1127 Cov.: 33 AF XY: 0.0361 AC XY: 26232 AN XY: 726742

African (AFR) AF: 0.00786 AC: 263 AN: 33472

American (AMR) AF: 0.0245 AC: 1096 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0318 AC: 831 AN: 26128

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39684

South Asian (SAS) AF: 0.0157 AC: 1356 AN: 86242

European-Finnish (FIN) AF: 0.0331 AC: 1767 AN: 53368

Middle Eastern (MID) AF: 0.0763 AC: 439 AN: 5754

European-Non Finnish (NFE) AF: 0.0413 AC: 45921 AN: 1111434

Other (OTH) AF: 0.0360 AC: 2176 AN: 60362

GnomAD4 genome AF: 0.0286 AC: 4364 AN: 152352 Hom.: 83 Cov.: 33 AF XY: 0.0284 AC XY: 2116 AN XY: 74494

African (AFR) AF: 0.00683 AC: 284 AN: 41584

American (AMR) AF: 0.0322 AC: 493 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 107 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4830

European-Finnish (FIN) AF: 0.0329 AC: 349 AN: 10618

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0419 AC: 2851 AN: 68026

Other (OTH) AF: 0.0411 AC: 87 AN: 2116

Alfa AF: 0.0363 Hom.: 83

Bravo AF: 0.0290

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0455

EpiControl AF: 0.0449

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.8
DANN	Benign	0.80
PhyloP100		-2.0
PromoterAI		0.031	Neutral
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2229716; hg19: chr12-57626582; COSMIC: COSV61074282; COSMIC: COSV61074282;