rs2311045

chr1-6440984-C-Gchr1-6440984-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031475.3(ESPN):c.909C>G(p.Arg303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,606,166 control chromosomes in the GnomAD database, including 15,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2335 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13328 hom.)
• Consequence: ESPN NM_031475.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.998

Genes affected

ESPN (HGNC:13281): (espin) This gene encodes a multifunctional actin-bundling protein. It plays a major role in regulating the organization, dimensions, dynamics, and signaling capacities of the actin filament-rich, microvillus-type specializations that mediate sensory transduction in various mechanosensory and chemosensory cells. Mutations in this gene are associated with autosomal recessive neurosensory deafness, and autosomal dominant sensorineural deafness without vestibular involvement. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-6440984-C-G is Benign according to our data. Variant chr1-6440984-C-G is described in ClinVar as [Benign]. Clinvar id is 226636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-6440984-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.998 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.909C>G	p.Arg303=	synonymous_variant	5/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.909C>G	p.Arg303=	synonymous_variant	5/13		NM_031475.3	P1
ESPN	ENST00000636330.1	c.909C>G	p.Arg303=	synonymous_variant	5/11	5
ESPN	ENST00000418286.1	c.264C>G	p.Arg88=	synonymous_variant	3/5	3

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25015 AN: 152018 Hom.: 2331 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.158

GnomAD3 exomes AF: 0.136 AC: 31699 AN: 232850 Hom.: 2344 AF XY: 0.138 AC XY: 17556 AN XY: 127514

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0837

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.157

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.132 AC: 191864 AN: 1454030 Hom.: 13328 Cov.: 37 AF XY: 0.133 AC XY: 96018 AN XY: 722742

Gnomad4 AFR exome AF: 0.260

Gnomad4 AMR exome AF: 0.0882

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.176

Gnomad4 SAS exome AF: 0.161

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.165 AC: 25041 AN: 152136 Hom.: 2335 Cov.: 32 AF XY: 0.164 AC XY: 12193 AN XY: 74370

Gnomad4 AFR AF: 0.249

Gnomad4 AMR AF: 0.119

Gnomad4 ASJ AF: 0.168

Gnomad4 EAS AF: 0.162

Gnomad4 SAS AF: 0.168

Gnomad4 FIN AF: 0.127

Gnomad4 NFE AF: 0.128

Gnomad4 OTH AF: 0.160

Alfa AF: 0.0845 Hom.: 157

Bravo AF: 0.169

Asia WGS AF: 0.165 AC: 570 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 2015	p.Arg303Arg in exon 5 of EPSN: This variant is not expected to have clinical sig nificance because it has high frequency in the general population, does not alte r an amino acid residue and is not located within the splice consensus sequence. It has been identified in 19.5% (14152/72600) of all chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org;dbSNP rs2311045). -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	8.1
Dann	Benign	0.90

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: rs2311045; hg19: chr1-6501044; COSMIC: COSV64704674; COSMIC: COSV64704674;