7-102554443-C-T

Variant names:

• chr7-102554443-C-T
• rs1438765775
• NM_001396242.1:c.245C>T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001396242.1(SPDYE2):​c.245C>T​(p.Pro82Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPDYE2 NM_001396242.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.653

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 -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05838579).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPDYE2	NM_001396242.1	c.245C>T	p.Pro82Leu	missense_variant	Exon 3 of 9	ENST00000691607.2	NP_001383171.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPDYE2	ENST00000691607.2	c.245C>T	p.Pro82Leu	missense_variant	Exon 3 of 9		NM_001396242.1	ENSP00000509749.1
ENSG00000270249	ENST00000514917.3	c.748+12139G>A		intron_variant	Intron 6 of 6	3		ENSP00000423309.4
POLR2J3	ENST00000513506.6	c.382+12139G>A		intron_variant	Intron 4 of 6	5		ENSP00000421085.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151988 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

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

GnomAD3 exomes AF: 0.0000196 AC: 1 AN: 51026 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 25686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000135

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000118 AC: 17 AN: 1441676 Hom.: 0 Cov.: 38 AF XY: 0.0000139 AC XY: 10 AN XY: 717276

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.0000228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000466

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000451

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000131 AC: 2 AN: 152106 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 74354

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000843 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.245C>T (p.P82L) alteration is located in exon 3 (coding exon 2) of the SPDYE2 gene. This alteration results from a C to T substitution at nucleotide position 245, causing the proline (P) at amino acid position 82 to be replaced by a leucine (L). 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	0.091
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	5.9
DANN	Benign	0.48
DEOGEN2	Benign	0.070	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.018	N
LIST_S2	Benign	0.35	.;T
M_CAP	Benign	0.0012	T
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.53	N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.028
Sift	Benign	0.33	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.0080	B;B
Vest4		0.17
MutPred		0.17		Loss of loop (P = 0.0084);Loss of loop (P = 0.0084);
MVP		0.11
ClinPred		0.051	T
Varity_R		0.070
gMVP		0.022

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: rs1438765775; hg19: chr7-102194890;