NM_001396242.1:c.442T>G

Variant names:

• chr7-102555962-T-G
• rs1453047874
• NM_001396242.1:c.442T>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001396242.1(SPDYE2):​c.442T>G​(p.Trp148Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000051 (0 hom., cov: 5)
  • Exomes 𝑓: 0.000067 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPDYE2 NM_001396242.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.661
• Publications: 0 publications found

Genes affected

SPDYE2 (HGNC:33841): (speedy/RINGO cell cycle regulator family member E2) Predicted to enable protein kinase binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000270249 (HGNC:):

POLR2J3 (HGNC:33853): (RNA polymerase II subunit J3) This gene is a member of the RNA polymerase II subunit 11 gene family, which includes three genes in a cluster on chromosome 7q22.1 and a pseudogene on chromosome 7p13. The founding member of this family, DNA directed RNA polymerase II polypeptide J, has been shown to encode a subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. This locus produces multiple, alternatively spliced transcripts that potentially express isoforms with distinct C-termini compared to DNA directed RNA polymerase II polypeptide J. Most or all variants are spliced to include additional non-coding exons at the 3' end which makes them candidates for nonsense-mediated decay (NMD). Consequently, it is not known if this locus expresses a protein or proteins in vivo. [provided by RefSeq, Jul 2008]

POLR2J3-UPK3BL2 (HGNC:58364):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06273991).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001396242.1. 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
	SPDYE2	NM_001396242.1	MANE Select	c.442T>G	p.Trp148Gly	missense	Exon 4 of 9	NP_001383171.1	Q495Y8-1
	SPDYE2	NM_001031618.3		c.442T>G	p.Trp148Gly	missense	Exon 4 of 9	NP_001026789.2	Q495Y8-1
	POLR2J3-UPK3BL2	NR_173351.1		n.464+11035A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPDYE2	ENST00000691607.2	MANE Select	c.442T>G	p.Trp148Gly	missense	Exon 4 of 9	ENSP00000509749.1	Q495Y8-1
	SPDYE2	ENST00000341656.5	TSL:1	c.10T>G	p.Trp4Gly	missense	Exon 1 of 6	ENSP00000342628.4	Q495Y8-2
	ENSG00000270249	ENST00000514917.3	TSL:3	c.748+10620A>C		intron	N/A	ENSP00000423309.4	H0Y980

Frequencies

GnomAD3 genomes AF: 0.0000509 AC: 2 AN: 39282 Hom.: 0 Cov.: 5

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000105

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000669 AC: 29 AN: 433570 Hom.: 2 Cov.: 5 AF XY: 0.0000400 AC XY: 9 AN XY: 224730

African (AFR) AF: 0.00 AC: 0 AN: 12030

American (AMR) AF: 0.00 AC: 0 AN: 17860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10762

East Asian (EAS) AF: 0.00 AC: 0 AN: 20438

South Asian (SAS) AF: 0.00 AC: 0 AN: 42554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 19892

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1602

European-Non Finnish (NFE) AF: 0.0000906 AC: 26 AN: 286958

Other (OTH) AF: 0.000140 AC: 3 AN: 21474

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000508 AC: 2 AN: 39352 Hom.: 0 Cov.: 5 AF XY: 0.00 AC XY: 0 AN XY: 18024

⚠️ 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: 11334

American (AMR) AF: 0.00 AC: 0 AN: 2986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 964

East Asian (EAS) AF: 0.00 AC: 0 AN: 888

South Asian (SAS) AF: 0.00 AC: 0 AN: 976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 114

European-Non Finnish (NFE) AF: 0.000105 AC: 2 AN: 19108

Other (OTH) AF: 0.00 AC: 0 AN: 462

⚠️ 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: 0.0000843 Hom.: 0

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	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	12
DANN	Benign	0.46
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0014	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.66
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.24	N
REVEL	Benign	0.051
Sift	Benign	0.46	T
Sift4G	Uncertain	0.030	D
Polyphen		0.050	B
Vest4		0.19
MutPred		0.22		Loss of helix (P = 0.0196)
MVP		0.061
ClinPred		0.061	T
PromoterAI		-0.0033	Neutral
Varity_R		0.13
gMVP		0.0055
Mutation Taster		=97/3	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: rs1453047874; hg19: chr7-102196409;