2-238100545-C-A

Variant names:

• chr2-238100545-C-A
• NM_194312.4:c.126C>A

Variant summary

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

The NM_194312.4(ESPNL):​c.126C>A​(p.His42Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,308 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ESPNL NM_194312.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.08

Genes affected

ESPNL (HGNC:27937): (espin like) Predicted to enable actin filament binding activity. Predicted to be involved in actin filament bundle assembly and sensory perception of sound. Predicted to be located in stereocilium tip. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
ESPNL	NM_194312.4	c.126C>A	p.His42Gln	missense_variant	Exon 1 of 9	ENST00000343063.8	NP_919288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ESPNL	ENST00000343063.8	c.126C>A	p.His42Gln	missense_variant	Exon 1 of 9	2	NM_194312.4	ENSP00000339115.3
ESPNL	ENST00000409169.5	c.126C>A	p.His42Gln	missense_variant	Exon 1 of 8	5		ENSP00000386577.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.94e-7 AC: 1 AN: 1440308 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 714692

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: 0.0000203

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.126C>A (p.H42Q) alteration is located in exon 1 (coding exon 1) of the ESPNL gene. This alteration results from a C to A substitution at nucleotide position 126, causing the histidine (H) at amino acid position 42 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.31	N
LIST_S2	Uncertain	0.92	D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.46	T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Uncertain	0.34
Sift	Benign	0.077	T;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.54
MutPred		0.37		Loss of methylation at R45 (P = 0.0525);Loss of methylation at R45 (P = 0.0525);
MVP		0.17
MPC		0.57
ClinPred		1.0	D
GERP RS		-2.0
Varity_R		0.34
gMVP		0.38

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: chr2-239009186;