rs121908136

chr1-6452092-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_031475.3(ESPN):c.2321G>A(p.Arg774Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,543,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.58

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 Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 1-6452092-G-A is Pathogenic according to our data. Variant chr1-6452092-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4422.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-6452092-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.36809248).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.2321G>A	p.Arg774Gln	missense_variant	10/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.2321G>A	p.Arg774Gln	missense_variant	10/13		NM_031475.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1390822 Hom.: 0 Cov.: 32 AF XY: 0.0000146 AC XY: 10 AN XY: 685558

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74366

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Deafness, without vestibular involvement, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.090	D
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;T;.;.;T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	2.0	M;.;M;.;.;.;.;.
MutationTaster	Benign	0.57	A;A;A
PrimateAI	Uncertain	0.49	T
Polyphen		0.92	P;.;P;.;P;.;.;.
Vest4		0.48, 0.54, 0.53
MutPred		0.12		Loss of methylation at K775 (P = 0.1106);Loss of methylation at K775 (P = 0.1106);Loss of methylation at K775 (P = 0.1106);.;.;.;.;.;
MVP		0.77
MPC		0.62
ClinPred		0.88	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.21

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: rs121908136; hg19: chr1-6512152; COSMIC: COSV64705277; COSMIC: COSV64705277;