14-93467669-A-T

Position:

• chr14-93467669-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 12P and 2B. PVS1 PP3_Strong BP6_Moderate

The NM_001395159.1(UNC79):​c.23-2A>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.098 (0 hom., cov: 0)
  • Exomes 𝑓: 0.19 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC79 NM_001395159.1 splice_acceptor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.29

Genes affected

UNC79 (HGNC:19966): (unc-79 homolog, NALCN channel complex subunit) The NALCN channel is responsible for Na(+) leak currents. The protein encoded by this gene, along with UNC80, is an accessory subunit of the NALCN channel that contributes to the Ca(2+) sensitivity of the channel. [provided by RefSeq, Sep 2016]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.3, offset of 11, new splice context is: tttatcttgttgcttccaAGatc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 14-93467669-A-T is Benign according to our data. Variant chr14-93467669-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3046520.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC79	NM_001395159.1	c.23-2A>T		splice_acceptor_variant		ENST00000695012.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC79	ENST00000695012.1	c.23-2A>T		splice_acceptor_variant			NM_001395159.1	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1482 AN: 15090 Hom.: 0 Cov.: 0 FAILED QC

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.0745

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0934

Gnomad SAS AF: 0.0979

Gnomad FIN AF: 0.0686

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.0921

Gnomad OTH AF: 0.0854

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.189 AC: 35105 AN: 185876 Hom.: 0 Cov.: 0 AF XY: 0.178 AC XY: 16445 AN XY: 92232

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0375

Gnomad4 ASJ exome AF: 0.0881

Gnomad4 EAS exome AF: 0.0346

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.0394

Gnomad4 NFE exome AF: 0.217

Gnomad4 OTH exome AF: 0.162

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0983 AC: 1486 AN: 15114 Hom.: 0 Cov.: 0 AF XY: 0.102 AC XY: 746 AN XY: 7304

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.0741

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.0928

Gnomad4 SAS AF: 0.0983

Gnomad4 FIN AF: 0.0686

Gnomad4 NFE AF: 0.0923

Gnomad4 OTH AF: 0.0882

ExAC AF: 0.177 AC: 2390

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

UNC79-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 29, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D;D;D
GERP RS		6.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.81		Position offset: 13
DS_AL_spliceai		0.98		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs778061554; hg19: chr14-93934015;