NM_194312.4:c.126C>A

Variant names:

• chr2-238100545-C-A
• rs376054274
• NM_194312.4:c.126C>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 publications found

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

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_194312.4. 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
	ESPNL	NM_194312.4	MANE Select	c.126C>A	p.His42Gln	missense	Exon 1 of 9	NP_919288.2	Q6ZVH7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ESPNL	ENST00000343063.8	TSL:2 MANE Select	c.126C>A	p.His42Gln	missense	Exon 1 of 9	ENSP00000339115.3	Q6ZVH7-1
	ESPNL	ENST00000409169.5	TSL:5	c.126C>A	p.His42Gln	missense	Exon 1 of 8	ENSP00000386577.1	Q6ZVH7-2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33028

American (AMR) AF: 0.00 AC: 0 AN: 41394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.00 AC: 0 AN: 38890

South Asian (SAS) AF: 0.00 AC: 0 AN: 83086

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104022

Other (OTH) AF: 0.00 AC: 0 AN: 59556

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L
PhyloP100		-1.1
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Uncertain	0.34
Sift	Benign	0.077	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.37		Loss of methylation at R45 (P = 0.0525)
MVP		0.17
MPC		0.57
ClinPred		1.0	D
GERP RS		-2.0
PromoterAI		-0.014	Neutral
Varity_R		0.34
gMVP		0.38
Mutation Taster		=85/15	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: rs376054274; hg19: chr2-239009186;