1-6425191-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031475.3(ESPN):c.236C>G(p.Ala79Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.16

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ESPN	NM_031475.3	c.236C>G	p.Ala79Gly	missense_variant	1/13	ENST00000645284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ESPN	ENST00000645284.1	c.236C>G	p.Ala79Gly	missense_variant	1/13		NM_031475.3	P1
ESPN	ENST00000636330.1	c.236C>G	p.Ala79Gly	missense_variant	1/11	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 22, 2022

This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with ESPN-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 79 of the ESPN protein (p.Ala79Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.0011	T
BayesDel_noAF	Benign	-0.24
Cadd	Pathogenic	28
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.9	L;.;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
Polyphen		1.0	D;.;D
Vest4		0.36
MutPred		0.34		Gain of catalytic residue at A79 (P = 0.0205);Gain of catalytic residue at A79 (P = 0.0205);Gain of catalytic residue at A79 (P = 0.0205);
MVP		0.63
MPC		0.64
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.47
gMVP		0.16

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: rs1642990503; hg19: chr1-6485251;