7-102561150-C-T

Variant names:

• chr7-102561150-C-T
• rs1199767083
• NM_001396242.1:c.1184C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001396242.1(SPDYE2):​c.1184C>T​(p.Ala395Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 5)
  • Exomes 𝑓: 0.000036 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPDYE2 NM_001396242.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.421

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.11522815).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE2	NM_001396242.1	c.1184C>T	p.Ala395Val	missense_variant	Exon 8 of 9	ENST00000691607.2	NP_001383171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDYE2	ENST00000691607.2	c.1184C>T	p.Ala395Val	missense_variant	Exon 8 of 9		NM_001396242.1	ENSP00000509749.1
ENSG00000270249	ENST00000514917.3	c.748+5432G>A		intron_variant	Intron 6 of 6	3		ENSP00000423309.4
POLR2J3	ENST00000513506.6	c.382+5432G>A		intron_variant	Intron 4 of 6	5		ENSP00000421085.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 2 AN: 45758 Hom.: 0 Cov.: 5 FAILED QC

Gnomad AFR AF: 0.0000919

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000359 AC: 12 AN: 334412 Hom.: 1 Cov.: 3 AF XY: 0.0000465 AC XY: 8 AN XY: 172008

Gnomad4 AFR exome AF: 0.000159

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0000955

Gnomad4 FIN exome AF: 0.0000759

Gnomad4 NFE exome AF: 0.0000142

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000437 AC: 2 AN: 45758 Hom.: 0 Cov.: 5 AF XY: 0.0000930 AC XY: 2 AN XY: 21506

Gnomad4 AFR AF: 0.0000919

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1184C>T (p.A395V) alteration is located in exon 8 (coding exon 7) of the SPDYE2 gene. This alteration results from a C to T substitution at nucleotide position 1184, causing the alanine (A) at amino acid position 395 to be replaced by a valine (V). 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	0.45
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T;T;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.67	.;T;.
M_CAP	Benign	0.0028	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-2.2	N;.;N
REVEL	Benign	0.066
Sift	Uncertain	0.019	D;.;D
Sift4G	Uncertain	0.036	D;D;T
Polyphen		0.97	D;D;.
Vest4		0.13
MutPred		0.27		Gain of sheet (P = 0.0477);Gain of sheet (P = 0.0477);.;
MVP		0.040
ClinPred		0.60	D
Varity_R		0.11
gMVP		0.020

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1199767083; hg19: chr7-102201597;