2-68866307-G-C

Variant names:

• chr2-68866307-G-C
• rs2231342
• NM_014482.3:c.599C>G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014482.3(BMP10):​c.599C>G​(p.Thr200Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00486 in 1,613,936 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.0038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (35 hom.)
• Consequence: BMP10 NM_014482.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.09

Genes affected

BMP10 (HGNC:20869): (bone morphogenetic protein 10) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate the mature protein, which binds to the activin receptor-like kinase 1 (ALK1) and plays important roles in cardiovascular development including cardiomyocyte proliferation and regulation of heart size, closure of the ductus arteriosus, angiogenesis and ventricular trabeculation. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008932412).
• BP6: Variant 2-68866307-G-C is Benign according to our data. Variant chr2-68866307-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3236724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 581 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BMP10	NM_014482.3	c.599C>G	p.Thr200Ser	missense_variant	Exon 2 of 2	ENST00000295379.2	NP_055297.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BMP10	ENST00000295379.2	c.599C>G	p.Thr200Ser	missense_variant	Exon 2 of 2	1	NM_014482.3	ENSP00000295379.1

Frequencies

GnomAD3 genomes AF: 0.00382 AC: 581 AN: 152020 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000677

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00353

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00520

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00468 AC: 1176 AN: 251176 Hom.: 10 AF XY: 0.00473 AC XY: 642 AN XY: 135726

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00487

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00563

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00496 AC: 7255 AN: 1461798 Hom.: 35 Cov.: 31 AF XY: 0.00488 AC XY: 3547 AN XY: 727204

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.00275

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00548

Gnomad4 FIN exome AF: 0.00912

Gnomad4 NFE exome AF: 0.00528

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.00382 AC: 581 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00429 AC XY: 319 AN XY: 74366

Gnomad4 AFR AF: 0.000675

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00353

Gnomad4 FIN AF: 0.0120

Gnomad4 NFE AF: 0.00521

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00449 Hom.: 0

Bravo AF: 0.00283

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00663 AC: 57

ExAC AF: 0.00492 AC: 597

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00379

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bladder exstrophy-epispadias-cloacal extrophy complex Benign:1

-

Obstetrics and Gynecology Department, Johns Hopkins School Of Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided Benign:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BMP10: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.86
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.0099
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.81	L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.10
Sift	Benign	0.37	T
Sift4G	Benign	0.52	T
Polyphen		0.0020	B
Vest4		0.038
MutPred		0.19		Loss of phosphorylation at T200 (P = 0.0754);
MVP		0.58
MPC		0.27
ClinPred		0.010	T
GERP RS		6.0
Varity_R		0.055
gMVP		0.27

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: rs2231342; hg19: chr2-69093439;