20-664183-C-G

Variant names:

• chr20-664183-C-G
• NM_033129.4:c.412G>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033129.4(SCRT2):​c.412G>C​(p.Ala138Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000109 in 914,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A138G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: SCRT2 NM_033129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.501

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065972745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCRT2	NM_033129.4	c.412G>C	p.Ala138Pro	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.412G>C	p.Ala138Pro	missense_variant	Exon 2 of 2	1	NM_033129.4	ENSP00000246104.5
ENSG00000270299	ENST00000488788.2	c.134-9863G>C		intron_variant	Intron 1 of 2	2		ENSP00000474279.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000109 AC: 1 AN: 914864 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 429202

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000123

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

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.412G>C (p.A138P) alteration is located in exon 2 (coding exon 2) of the SCRT2 gene. This alteration results from a G to C substitution at nucleotide position 412, causing the alanine (A) at amino acid position 138 to be replaced by a proline (P). 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	0.11
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	7.1
DANN	Benign	0.85
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.84	N
REVEL	Benign	0.072
Sift	Benign	0.23	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.35		Loss of helix (P = 0.0376);
MVP		0.014
MPC		1.7
ClinPred		0.040	T
GERP RS		-2.0
Varity_R		0.044
gMVP		0.28

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-644827;