chr1-6451926-A-C

Variant names:

• chr1-6451926-A-C
• rs121908134
• NM_031475.3:c.2155A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP5

The NM_031475.3(ESPN):​c.2155A>C​(p.Ser719Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,458,666 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.11
• Publications: 4 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):

• nonsyndromic genetic hearing loss

  Inheritance: AD, AR Classification: DEFINITIVE, LIMITED Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 36

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• 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: AR, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP5: Variant 1-6451926-A-C is Pathogenic according to our data. Variant chr1-6451926-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 4420.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	NM_031475.3	MANE Select	c.2155A>C	p.Ser719Arg	missense	Exon 10 of 13	NP_113663.2
	ESPN	NM_001367474.1		c.2092A>C	p.Ser698Arg	missense	Exon 12 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.2065A>C	p.Ser689Arg	missense	Exon 11 of 14	NP_001354402.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.2155A>C	p.Ser719Arg	missense	Exon 10 of 13	ENSP00000496593.1
	ESPN	ENST00000461727.6	TSL:1	c.457A>C	p.Ser153Arg	missense	Exon 5 of 8	ENSP00000465308.1
	ESPN	ENST00000636330.1	TSL:5	c.2155A>C	p.Ser719Arg	missense	Exon 10 of 11	ENSP00000490186.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 243942 AF XY: 0.00000755

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1458666 Hom.: 0 Cov.: 32 AF XY: 0.00000551 AC XY: 4 AN XY: 725382

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 85618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52596

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5702

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1110862

Other (OTH) AF: 0.00 AC: 0 AN: 60266

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000278 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Deafness, without vestibular involvement, autosomal dominant Pathogenic:1

Feb 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.018
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	1.8	L
PhyloP100		2.1
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.17	T
Polyphen		0.76	P
Vest4		0.33
MutPred		0.47		Loss of glycosylation at S719 (P = 0.0017)
MVP		0.75
MPC		0.50
ClinPred		0.95	D
GERP RS		4.0
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.23
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs121908134; hg19: chr1-6511986;