20-664177-C-T

Variant names:

• chr20-664177-C-T
• rs1984069294
• NM_033129.4:c.418G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_033129.4(SCRT2):​c.418G>A​(p.Gly140Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 893,486 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: SCRT2 NM_033129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59

Genes affected

SCRT2 (HGNC:15952): (scratch family transcriptional repressor 2) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in negative regulation of extrinsic apoptotic signaling pathway via death domain receptors and negative regulation of transcription by RNA polymerase II. Predicted to act upstream of or within regulation of neuron migration. Predicted to be located in chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000270299 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07328209).
• BS2: High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCRT2	NM_033129.4	c.418G>A	p.Gly140Arg	missense_variant	Exon 2 of 2	ENST00000246104.7	NP_149120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCRT2	ENST00000246104.7	c.418G>A	p.Gly140Arg	missense_variant	Exon 2 of 2	1	NM_033129.4	ENSP00000246104.5
ENSG00000270299	ENST00000488788.2	c.134-9857G>A		intron_variant	Intron 1 of 2	2		ENSP00000474279.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000459 AC: 41 AN: 893486 Hom.: 0 Cov.: 28 AF XY: 0.0000430 AC XY: 18 AN XY: 418394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000168

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000474

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.418G>A (p.G140R) alteration is located in exon 2 (coding exon 2) of the SCRT2 gene. This alteration results from a G to A substitution at nucleotide position 418, causing the glycine (G) at amino acid position 140 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	Uncertain	0.36
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.17	N
REVEL	Benign	0.061
Sift	Benign	0.49	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.10
MutPred		0.34		Gain of methylation at G140 (P = 0.0158);
MVP		0.055
MPC		1.4
ClinPred		0.088	T
GERP RS		3.5
Varity_R		0.096
gMVP		0.27

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: rs1984069294; hg19: chr20-644821;