1-6451891-C-G

Variant names:

• chr1-6451891-C-G
• rs576917953
• NM_031475.3:c.2120C>G

Variant summary

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

The NM_031475.3(ESPN):​c.2120C>G​(p.Pro707Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,458,602 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. P707L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.243
• 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: 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

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.2120C>G	p.Pro707Arg	missense	Exon 10 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.2057C>G	p.Pro686Arg	missense	Exon 12 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.2030C>G	p.Pro677Arg	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.2120C>G	p.Pro707Arg	missense	Exon 10 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000461727.6	TSL:1	c.422C>G	p.Pro141Arg	missense	Exon 5 of 8	ENSP00000465308.1	B1AK53-2
	ESPN	ENST00000636330.1	TSL:5	c.2120C>G	p.Pro707Arg	missense	Exon 10 of 11	ENSP00000490186.1	A0A1B0GUN9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1458602 Hom.: 0 Cov.: 32 AF XY: 0.00000414 AC XY: 3 AN XY: 725382

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.00 AC: 0 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110840

Other (OTH) AF: 0.00 AC: 0 AN: 60254

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.9	L
PhyloP100		0.24
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.29
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.35
MutPred		0.22		Loss of glycosylation at P707 (P = 0.0221)
MVP		0.79
MPC		0.62
ClinPred		0.98	D
GERP RS		4.2
PromoterAI		0.0093	Neutral
Varity_R		0.39
gMVP		0.21
Mutation Taster		=77/23	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

Other links and lift over

dbSNP: rs576917953; hg19: chr1-6511951;