1-6451928-C-A

Variant names:

• chr1-6451928-C-A
• NM_031475.3:c.2157C>A
• ESPN p.Ser719Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PS1 PM2

The NM_031475.3(ESPN):​c.2157C>A​(p.Ser719Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.59
• Publications: 0 publications found

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]

ESPN Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 36

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• nonsyndromic genetic hearing loss

  Inheritance: AR, AD Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Usher syndrome, type 1M

  Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PS1: Transcript NM_031475.3 (ESPN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_031475.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	NM_031475.3	MANE Select	c.2157C>A	p.Ser719Arg	missense	Exon 10 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.2094C>A	p.Ser698Arg	missense	Exon 12 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.2067C>A	p.Ser689Arg	missense	Exon 11 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.2157C>A	p.Ser719Arg	missense	Exon 10 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000461727.6	TSL:1	c.459C>A	p.Ser153Arg	missense	Exon 5 of 8	ENSP00000465308.1	B1AK53-2
	ESPN	ENST00000636330.1	TSL:5	c.2157C>A	p.Ser719Arg	missense	Exon 10 of 11	ENSP00000490186.1	A0A1B0GUN9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.17	T
PromoterAI		-0.0039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.23
Mutation Taster		=79/21	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-6511988;