chr2-65313953-C-A

Variant names:

• chr2-65313953-C-A
• rs146072471
• NM_181784.3:c.805G>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_181784.3(SPRED2):​c.805G>T​(p.Val269Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00186 in 1,612,116 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: SPRED2 NM_181784.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.04
• Publications: 7 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: Benign. The variant received -9 ACMG points.

• 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=0.008644044).
• BP6: Variant 2-65313953-C-A is Benign according to our data. Variant chr2-65313953-C-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3770697.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.805G>T	p.Val269Leu	missense	Exon 6 of 6	NP_861449.2	Q7Z698-1
	SPRED2	NM_001128210.2		c.796G>T	p.Val266Leu	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.805G>T	p.Val269Leu	missense	Exon 6 of 6	ENSP00000348753.4	Q7Z698-1
	SPRED2	ENST00000452315.5	TSL:1	c.850G>T	p.Val284Leu	missense	Exon 6 of 6	ENSP00000390595.1	C9JG63
	SPRED2	ENST00000443619.6	TSL:2	c.796G>T	p.Val266Leu	missense	Exon 6 of 6	ENSP00000393697.2	Q7Z698-2

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152208 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00152 AC: 378 AN: 247876 AF XY: 0.00153

Gnomad AFR exome AF: 0.000315

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00244

Gnomad OTH exome AF: 0.000984

GnomAD4 exome AF: 0.00191 AC: 2789 AN: 1459790 Hom.: 6 Cov.: 34 AF XY: 0.00192 AC XY: 1397 AN XY: 726348

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86258

European-Finnish (FIN) AF: 0.00444 AC: 228 AN: 51366

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00218 AC: 2426 AN: 1111982

Other (OTH) AF: 0.00131 AC: 79 AN: 60378

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152326 Hom.: 2 Cov.: 33 AF XY: 0.00142 AC XY: 106 AN XY: 74482

African (AFR) AF: 0.000337 AC: 14 AN: 41588

American (AMR) AF: 0.000458 AC: 7 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00377 AC: 40 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68020

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00182 Hom.: 1

Bravo AF: 0.00105

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00169 AC: 205

EpiCase AF: 0.00174

EpiControl AF: 0.00261

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.7	L
PhyloP100		3.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.71	T
Polyphen		0.049	B
Vest4		0.37
MutPred		0.078		Gain of phosphorylation at S272 (P = 0.1757)
MVP		0.83
MPC		0.84
ClinPred		0.015	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.5
Varity_R		0.074
gMVP		0.52
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146072471; hg19: chr2-65541087; COSMIC: COSV100710388; COSMIC: COSV100710388;