20-664161-G-T

Variant names:

• chr20-664161-G-T
• rs769356884
• NM_033129.4:c.434C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033129.4(SCRT2):​c.434C>A​(p.Ala145Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,070,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: SCRT2 NM_033129.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0779061).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033129.4. 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
	SCRT2	NM_033129.4	MANE Select	c.434C>A	p.Ala145Glu	missense	Exon 2 of 2	NP_149120.1	Q9NQ03

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SCRT2	ENST00000246104.7	TSL:1 MANE Select	c.434C>A	p.Ala145Glu	missense	Exon 2 of 2	ENSP00000246104.5	Q9NQ03
	ENSG00000270299	ENST00000488788.2	TSL:2	c.134-9841C>A		intron	N/A	ENSP00000474279.1	S4R3F8
	ENSG00000298442	ENST00000755524.1		n.179+3263G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000685 AC: 1 AN: 145888 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 1996 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000216 AC: 2 AN: 924484 Hom.: 0 Cov.: 30 AF XY: 0.00000230 AC XY: 1 AN XY: 434626

African (AFR) AF: 0.00 AC: 0 AN: 17818

American (AMR) AF: 0.00 AC: 0 AN: 3654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 7744

East Asian (EAS) AF: 0.00 AC: 0 AN: 10858

South Asian (SAS) AF: 0.0000550 AC: 1 AN: 18196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2102

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 820058

Other (OTH) AF: 0.0000306 AC: 1 AN: 32684

GnomAD4 genome AF: 0.00000685 AC: 1 AN: 145994 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 1 AN XY: 71080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40746

American (AMR) AF: 0.00 AC: 0 AN: 14736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3366

East Asian (EAS) AF: 0.00 AC: 0 AN: 5078

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65664

Other (OTH) AF: 0.00 AC: 0 AN: 2030

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000169 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	11
DANN	Benign	0.83
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	0.020	N
REVEL	Benign	0.086
Sift	Benign	0.55	T
Sift4G	Benign	0.98	T
Polyphen		0.68	P
Vest4		0.14
MutPred		0.42		Loss of MoRF binding (P = 0.0408)
MVP		0.11
MPC		1.3
ClinPred		0.11	T
GERP RS		1.3
Varity_R		0.063
gMVP		0.22
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs769356884; hg19: chr20-644805;