20-6778468-A-T

Position:

• chr20-6778468-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001200.4(BMP2):​c.570A>T​(p.Arg190Ser) variant causes a missense change. The variant allele was found at a frequency of 0.643 in 1,613,906 control chromosomes in the GnomAD database, including 339,264 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.72 (41279 hom., cov: 32)
  • Exomes 𝑓: 0.63 (297985 hom.)
• Consequence: BMP2 NM_001200.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.90

Genes affected

BMP2 (HGNC:1069): (bone morphogenetic protein 2) 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 each subunit of the disulfide-linked homodimer, which plays a role in bone and cartilage development. Duplication of a regulatory region downstream of this gene causes a form of brachydactyly characterized by a malformed index finger and second toe in human patients. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.7473716E-6).
• BP6: Variant 20-6778468-A-T is Benign according to our data. Variant chr20-6778468-A-T is described in ClinVar as [Benign]. Clinvar id is 196322.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.92 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BMP2	NM_001200.4	c.570A>T	p.Arg190Ser	missense_variant	3/3	ENST00000378827.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BMP2	ENST00000378827.5	c.570A>T	p.Arg190Ser	missense_variant	3/3	1	NM_001200.4	P1

Frequencies

GnomAD3 genomes AF: 0.723 AC: 109818 AN: 151950 Hom.: 41224 Cov.: 32

Gnomad AFR AF: 0.928

Gnomad AMI AF: 0.630

Gnomad AMR AF: 0.716

Gnomad ASJ AF: 0.820

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.613

Gnomad FIN AF: 0.571

Gnomad MID AF: 0.763

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.734

GnomAD3 exomes AF: 0.671 AC: 168344 AN: 250820 Hom.: 57711 AF XY: 0.662 AC XY: 89964 AN XY: 135812

Gnomad AFR exome AF: 0.936

Gnomad AMR exome AF: 0.696

Gnomad ASJ exome AF: 0.812

Gnomad EAS exome AF: 0.819

Gnomad SAS exome AF: 0.605

Gnomad FIN exome AF: 0.574

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.684

GnomAD4 exome AF: 0.635 AC: 928160 AN: 1461838 Hom.: 297985 Cov.: 81 AF XY: 0.634 AC XY: 461020 AN XY: 727222

Gnomad4 AFR exome AF: 0.941

Gnomad4 AMR exome AF: 0.700

Gnomad4 ASJ exome AF: 0.810

Gnomad4 EAS exome AF: 0.813

Gnomad4 SAS exome AF: 0.609

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.615

Gnomad4 OTH exome AF: 0.670

GnomAD4 genome AF: 0.723 AC: 109929 AN: 152068 Hom.: 41279 Cov.: 32 AF XY: 0.719 AC XY: 53404 AN XY: 74320

Gnomad4 AFR AF: 0.928

Gnomad4 AMR AF: 0.716

Gnomad4 ASJ AF: 0.820

Gnomad4 EAS AF: 0.813

Gnomad4 SAS AF: 0.612

Gnomad4 FIN AF: 0.571

Gnomad4 NFE AF: 0.620

Gnomad4 OTH AF: 0.736

Alfa AF: 0.659 Hom.: 10683

Bravo AF: 0.744

TwinsUK AF: 0.629 AC: 2331

ALSPAC AF: 0.626 AC: 2412

ESP6500AA AF: 0.928 AC: 4086

ESP6500EA AF: 0.628 AC: 5398

ExAC AF: 0.675 AC: 81894

Asia WGS AF: 0.733 AC: 2546 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 21, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 16, 2018	This variant is associated with the following publications: (PMID: 31640930, 26460254, 23506588) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0000027	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.5	M
MutationTaster	Benign	6.4e-7	P
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.41
Sift	Benign	0.096	T
Sift4G	Uncertain	0.019	D
Polyphen		0.98	D
Vest4		0.32
MutPred		0.29		Gain of ubiquitination at K185 (P = 0.0445);
MPC		1.3
ClinPred		0.043	T
GERP RS		5.7
Varity_R		0.76
gMVP		0.70

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: rs235768; hg19: chr20-6759115; COSMIC: COSV66578820;