chr1-6440984-C-G

Variant names:

• chr1-6440984-C-G
• rs2311045
• NM_031475.3:c.909C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_031475.3(ESPN):​c.909C>G​(p.Arg303Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.135 in 1,606,166 control chromosomes in the GnomAD database, including 15,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2335 hom., cov: 32)
  • Exomes 𝑓: 0.13 (13328 hom.)
• Consequence: ESPN NM_031475.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.998
• Publications: 13 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-6440984-C-G is Benign according to our data. Variant chr1-6440984-C-G is described in ClinVar as Benign. ClinVar VariationId is 226636.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.998 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

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.909C>G	p.Arg303Arg	synonymous	Exon 5 of 13	NP_113663.2	B1AK53-1
	ESPN	NM_001367474.1		c.909C>G	p.Arg303Arg	synonymous	Exon 5 of 15	NP_001354403.1
	ESPN	NM_001367473.1		c.909C>G	p.Arg303Arg	synonymous	Exon 5 of 14	NP_001354402.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPN	ENST00000645284.1	MANE Select	c.909C>G	p.Arg303Arg	synonymous	Exon 5 of 13	ENSP00000496593.1	B1AK53-1
	ESPN	ENST00000636330.1	TSL:5	c.909C>G	p.Arg303Arg	synonymous	Exon 5 of 11	ENSP00000490186.1	A0A1B0GUN9
	ESPN	ENST00000418286.1	TSL:3	c.264C>G	p.Arg88Arg	synonymous	Exon 3 of 5	ENSP00000401793.1	Q5JYL1

Frequencies

GnomAD3 genomes AF: 0.165 AC: 25015 AN: 152018 Hom.: 2331 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.168

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.168

Gnomad FIN AF: 0.127

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.158

GnomAD2 exomes AF: 0.136 AC: 31699 AN: 232850 AF XY: 0.138

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0837

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.157

Gnomad FIN exome AF: 0.125

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.135

GnomAD4 exome AF: 0.132 AC: 191864 AN: 1454030 Hom.: 13328 Cov.: 37 AF XY: 0.133 AC XY: 96018 AN XY: 722742

African (AFR) AF: 0.260 AC: 8658 AN: 33348

American (AMR) AF: 0.0882 AC: 3883 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4663 AN: 25908

East Asian (EAS) AF: 0.176 AC: 6952 AN: 39410

South Asian (SAS) AF: 0.161 AC: 13682 AN: 85190

European-Finnish (FIN) AF: 0.124 AC: 6387 AN: 51654

Middle Eastern (MID) AF: 0.190 AC: 971 AN: 5120

European-Non Finnish (NFE) AF: 0.125 AC: 138186 AN: 1109400

Other (OTH) AF: 0.141 AC: 8482 AN: 59994

GnomAD4 genome AF: 0.165 AC: 25041 AN: 152136 Hom.: 2335 Cov.: 32 AF XY: 0.164 AC XY: 12193 AN XY: 74370

African (AFR) AF: 0.249 AC: 10346 AN: 41498

American (AMR) AF: 0.119 AC: 1820 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 585 AN: 3472

East Asian (EAS) AF: 0.162 AC: 833 AN: 5152

South Asian (SAS) AF: 0.168 AC: 812 AN: 4828

European-Finnish (FIN) AF: 0.127 AC: 1344 AN: 10612

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.128 AC: 8732 AN: 67954

Other (OTH) AF: 0.160 AC: 337 AN: 2110

Alfa AF: 0.0845 Hom.: 157

Bravo AF: 0.169

Asia WGS AF: 0.165 AC: 570 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	8.1
DANN	Benign	0.90
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2311045; hg19: chr1-6501044; COSMIC: COSV64704674; COSMIC: COSV64704674;