2-65314124-C-T

Variant names:

• chr2-65314124-C-T
• NM_181784.3:c.634G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_181784.3(SPRED2):​c.634G>A​(p.Glu212Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,932 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SPRED2 NM_181784.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83

Genes affected

SPRED2 (HGNC:17722): (sprouty related EVH1 domain containing 2) SPRED2 is a member of the Sprouty (see SPRY1; MIM 602465)/SPRED family of proteins that regulate growth factor-induced activation of the MAP kinase cascade (see MAPK1; MIM 176948) (Nonami et al., 2004 [PubMed 15465815]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPRED2	NM_181784.3	c.634G>A	p.Glu212Lys	missense_variant	Exon 6 of 6	ENST00000356388.9	NP_861449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPRED2	ENST00000356388.9	c.634G>A	p.Glu212Lys	missense_variant	Exon 6 of 6	1	NM_181784.3	ENSP00000348753.4
SPRED2	ENST00000452315.5	c.679G>A	p.Glu227Lys	missense_variant	Exon 6 of 6	1		ENSP00000390595.1
SPRED2	ENST00000443619.6	c.625G>A	p.Glu209Lys	missense_variant	Exon 6 of 6	2		ENSP00000393697.2
SPRED2	ENST00000421087.5	c.280G>A	p.Glu94Lys	missense_variant	Exon 3 of 3	3		ENSP00000407627.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452932 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 720632

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.634G>A (p.E212K) alteration is located in exon 6 (coding exon 6) of the SPRED2 gene. This alteration results from a G to A substitution at nucleotide position 634, causing the glutamic acid (E) at amino acid position 212 to be replaced by a lysine (K). 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	0.35
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	T;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Benign	0.066	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	-0.054	T
MutationAssessor	Uncertain	2.4	M;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.062	T;T;T;D
Sift4G	Benign	0.16	T;T;.;.
Polyphen		0.98	D;.;.;.
Vest4		0.42
MutPred		0.46		Gain of sheet (P = 0.0061);.;.;.;
MVP		0.93
MPC		1.8
ClinPred		0.95	D
GERP RS		5.3
Varity_R		0.23
gMVP		0.84

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: chr2-65541258;