2-65313804-G-C

Variant names:

• chr2-65313804-G-C
• rs771529653
• NM_181784.3:c.954C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_181784.3(SPRED2):​c.954C>G​(p.His318Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H318H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPRED2 NM_181784.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.139
• Publications: 1 publications found

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]

SPRED2 Gene-Disease associations (from GenCC):

• Noonan syndrome 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 1 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.3079 (below the threshold of 3.09). Trascript score misZ: 0.70292 (below the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome 14.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22996372).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181784.3. 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
	SPRED2	NM_181784.3	MANE Select	c.954C>G	p.His318Gln	missense	Exon 6 of 6	NP_861449.2	Q7Z698-1
	SPRED2	NM_001128210.2		c.945C>G	p.His315Gln	missense	Exon 6 of 6	NP_001121682.1	Q7Z698-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPRED2	ENST00000356388.9	TSL:1 MANE Select	c.954C>G	p.His318Gln	missense	Exon 6 of 6	ENSP00000348753.4	Q7Z698-1
	SPRED2	ENST00000452315.5	TSL:1	c.999C>G	p.His333Gln	missense	Exon 6 of 6	ENSP00000390595.1	C9JG63
	SPRED2	ENST00000443619.6	TSL:2	c.945C>G	p.His315Gln	missense	Exon 6 of 6	ENSP00000393697.2	Q7Z698-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.84	L
PhyloP100		0.14
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.51	T
Polyphen		0.072	B
Vest4		0.14
MutPred		0.46		Loss of loop (P = 0.0112)
MVP		0.78
MPC		0.93
ClinPred		0.57	D
GERP RS		0.84
Varity_R		0.16
gMVP		0.15
Mutation Taster		=73/27	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: rs771529653; hg19: chr2-65540938;