chr2-62993545-C-G

Position:

• chr2-62993545-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The ENST00000431489.6(EHBP1):​c.2749C>G​(p.Leu917Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,594,258 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L917P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: EHBP1 ENST00000431489.6 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.34

Genes affected

EHBP1 (HGNC:29144): (EH domain binding protein 1) This gene encodes an Eps15 homology domain binding protein. The encoded protein may play a role in endocytic trafficking. A single nucleotide polymorphism in this gene is associated with an aggressive form of prostate cancer. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Feb 2010]

EHBP1-AS1 (HGNC:55766): (EHBP1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011664897).
• BP6: Variant 2-62993545-C-G is Benign according to our data. Variant chr2-62993545-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3053880.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 125 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EHBP1	NM_001142616.3	c.2749C>G	p.Leu917Val	missense_variant	17/23	ENST00000431489.6	NP_001136088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EHBP1	ENST00000431489.6	c.2749C>G	p.Leu917Val	missense_variant	17/23	1	NM_001142616.3	ENSP00000403783	A1
EHBP1-AS1	ENST00000650490.1	n.572+20014G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151914 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000394

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000190

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00143

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00101 AC: 250 AN: 247598 Hom.: 0 AF XY: 0.00108 AC XY: 145 AN XY: 133972

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.000509

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00142

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.000669

GnomAD4 exome AF: 0.00124 AC: 1788 AN: 1442228 Hom.: 1 Cov.: 30 AF XY: 0.00125 AC XY: 899 AN XY: 717576

Gnomad4 AFR exome AF: 0.000211

Gnomad4 AMR exome AF: 0.000498

Gnomad4 ASJ exome AF: 0.000314

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00195

Gnomad4 FIN exome AF: 0.000285

Gnomad4 NFE exome AF: 0.00138

Gnomad4 OTH exome AF: 0.000826

GnomAD4 genome AF: 0.000822 AC: 125 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.000781 AC XY: 58 AN XY: 74310

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000393

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.000190

Gnomad4 NFE AF: 0.00143

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000725

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000980 AC: 119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EHBP1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.010	.;.;T;.
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	.;D;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	.;.;N;.
MutationTaster	Benign	0.76	D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.54	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.46	T;T;T;T
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.33	B;B;B;B
Vest4		0.14
MVP		0.43
MPC		0.10
ClinPred		0.028	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.10
gMVP		0.23

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: rs150215775; hg19: chr2-63220680; COSMIC: COSV99066857;