2-65313808-T-A

Position:

• chr2-65313808-T-A

Variant summary

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

The NM_181784.3(SPRED2):​c.950A>T​(p.Asn317Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,592 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SPRED2 NM_181784.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.14

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/exons	MANE	Protein	UniProt
SPRED2	NM_181784.3	c.950A>T	p.Asn317Ile	missense_variant	6/6	ENST00000356388.9	NP_861449.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPRED2	ENST00000356388.9	c.950A>T	p.Asn317Ile	missense_variant	6/6	1	NM_181784.3	ENSP00000348753.4
SPRED2	ENST00000452315.5	c.995A>T	p.Asn332Ile	missense_variant	6/6	1		ENSP00000390595.1
SPRED2	ENST00000443619.6	c.941A>T	p.Asn314Ile	missense_variant	6/6	2		ENSP00000393697.2
SPRED2	ENST00000421087.5	c.596A>T	p.Asn199Ile	missense_variant	3/3	3		ENSP00000407627.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461592 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2023

The c.950A>T (p.N317I) alteration is located in exon 6 (coding exon 6) of the SPRED2 gene. This alteration results from a A to T substitution at nucleotide position 950, causing the asparagine (N) at amino acid position 317 to be replaced by an isoleucine (I). 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	0.41
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.86	D;.;D;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.8	M;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.049	D;D;.;.
Polyphen		0.095	B;.;.;.
Vest4		0.62
MutPred		0.56		Gain of sheet (P = 0.0125);.;.;.;
MVP		0.88
MPC		1.8
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.46
gMVP		0.67

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: rs936514564; hg19: chr2-65540942;