chr1-6424981-C-G

Position:

• chr1-6424981-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_031475.3(ESPN):​c.26C>G​(p.Ala9Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000153 in 1,305,310 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: ESPN NM_031475.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.36

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ESPN	NM_031475.3	c.26C>G	p.Ala9Gly	missense_variant	1/13	ENST00000645284.1	NP_113663.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ESPN	ENST00000645284.1	c.26C>G	p.Ala9Gly	missense_variant	1/13		NM_031475.3	ENSP00000496593	P1
ESPN	ENST00000636330.1	c.26C>G	p.Ala9Gly	missense_variant	1/11	5		ENSP00000490186

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000153 AC: 2 AN: 1305310 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 643434

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000192

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 25, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Pathogenic	0.85	D
MetaRNN	Uncertain	0.70	D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.2	H;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.6	.;.;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.012	.;.;D
Sift4G	Uncertain	0.011	.;.;D
Polyphen		1.0	D;.;D
Vest4		0.68
MutPred		0.46		Gain of disorder (P = 0.3055);Gain of disorder (P = 0.3055);Gain of disorder (P = 0.3055);
MVP		0.65
MPC		0.63
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.66
gMVP		0.45

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-6485041;