chr1-6452001-G-C

Variant names:

• chr1-6452001-G-C
• rs121908135
• NM_031475.3:c.2230G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_031475.3(ESPN):​c.2230G>C​(p.Asp744His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,094 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D744N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.71
• 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):

• 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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ESPN	NM_031475.3	c.2230G>C	p.Asp744His	missense_variant	Exon 10 of 13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.2230G>C	p.Asp744His	missense_variant	Exon 10 of 13		NM_031475.3	ENSP00000496593.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453094 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722260

African (AFR) AF: 0.00 AC: 0 AN: 33294

American (AMR) AF: 0.00 AC: 0 AN: 43906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25970

East Asian (EAS) AF: 0.00 AC: 0 AN: 39334

South Asian (SAS) AF: 0.00 AC: 0 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107738

Other (OTH) AF: 0.00 AC: 0 AN: 60046

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;T;D;T;.;.;T;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	2.0	M;.;M;.;.;.;.;.
PhyloP100		9.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.5	.;.;D;D;.;.;.;.
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.
Sift4G	Uncertain	0.0040	.;.;D;T;T;.;D;.
Polyphen		1.0	D;.;D;.;D;.;.;.
Vest4		0.67, 0.92, 0.92
MutPred		0.21		Gain of MoRF binding (P = 0.0663);Gain of MoRF binding (P = 0.0663);Gain of MoRF binding (P = 0.0663);.;.;.;.;.;
MVP		0.86
MPC		0.69
ClinPred		1.0	D
GERP RS		5.1
PromoterAI		-0.0030	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.50
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs121908135; hg19: chr1-6512061;