chr14-77562460-A-G

Position:

• chr14-77562460-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004863.4(SPTLC2):​c.786T>C​(p.Asn262Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.917 in 1,613,902 control chromosomes in the GnomAD database, including 682,406 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (55355 hom., cov: 32)
  • Exomes 𝑓: 0.92 (627051 hom.)
• Consequence: SPTLC2 NM_004863.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.570

Genes affected

SPTLC2 (HGNC:11278): (serine palmitoyltransferase long chain base subunit 2) This gene encodes a long chain base subunit of serine palmitoyltransferase. Serine palmitoyltransferase, which consists of two different subunits, is the key enzyme in sphingolipid biosynthesis. It catalyzes the pyridoxal-5-prime-phosphate-dependent condensation of L-serine and palmitoyl-CoA to 3-oxosphinganine. Mutations in this gene were identified in patients with hereditary sensory neuropathy type I. [provided by RefSeq, Mar 2011]

SPTLC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 14-77562460-A-G is Benign according to our data. Variant chr14-77562460-A-G is described in ClinVar as [Benign]. Clinvar id is 314672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77562460-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.967 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC2	NM_004863.4	c.786T>C	p.Asn262Asn	synonymous_variant	6/12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3	c.786T>C	p.Asn262Asn	synonymous_variant	6/10		XP_011535686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7	c.786T>C	p.Asn262Asn	synonymous_variant	6/12	1	NM_004863.4	ENSP00000216484.2

Frequencies

GnomAD3 genomes AF: 0.842 AC: 127992 AN: 152080 Hom.: 55335 Cov.: 32

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.969

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.960

Gnomad EAS AF: 0.990

Gnomad SAS AF: 0.960

Gnomad FIN AF: 0.944

Gnomad MID AF: 0.965

Gnomad NFE AF: 0.934

Gnomad OTH AF: 0.877

GnomAD3 exomes AF: 0.904 AC: 227343 AN: 251412 Hom.: 103962 AF XY: 0.916 AC XY: 124480 AN XY: 135876

Gnomad AFR exome AF: 0.620

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.961

Gnomad EAS exome AF: 0.995

Gnomad SAS exome AF: 0.965

Gnomad FIN exome AF: 0.945

Gnomad NFE exome AF: 0.933

Gnomad OTH exome AF: 0.926

GnomAD4 exome AF: 0.924 AC: 1351243 AN: 1461704 Hom.: 627051 Cov.: 50 AF XY: 0.927 AC XY: 674395 AN XY: 727156

Gnomad4 AFR exome AF: 0.606

Gnomad4 AMR exome AF: 0.801

Gnomad4 ASJ exome AF: 0.959

Gnomad4 EAS exome AF: 0.996

Gnomad4 SAS exome AF: 0.965

Gnomad4 FIN exome AF: 0.943

Gnomad4 NFE exome AF: 0.932

Gnomad4 OTH exome AF: 0.922

GnomAD4 genome AF: 0.841 AC: 128067 AN: 152198 Hom.: 55355 Cov.: 32 AF XY: 0.845 AC XY: 62895 AN XY: 74436

Gnomad4 AFR AF: 0.622

Gnomad4 AMR AF: 0.823

Gnomad4 ASJ AF: 0.960

Gnomad4 EAS AF: 0.990

Gnomad4 SAS AF: 0.960

Gnomad4 FIN AF: 0.944

Gnomad4 NFE AF: 0.934

Gnomad4 OTH AF: 0.878

Alfa AF: 0.920 Hom.: 100120

Bravo AF: 0.825

Asia WGS AF: 0.952 AC: 3311 AN: 3478

EpiCase AF: 0.937

EpiControl AF: 0.936

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuropathy, hereditary sensory and autonomic, type 1C Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 26, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

LitVar

Other links and lift over

dbSNP: rs2364602; hg19: chr14-78028803;