chr14-77597351-T-G

Position:

• chr14-77597351-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004863.4(SPTLC2):​c.162A>C​(p.Leu54Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,614,158 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0096 (22 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (26 hom.)
• Consequence: SPTLC2 NM_004863.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.560

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=-0.59).
• BP6: Variant 14-77597351-T-G is Benign according to our data. Variant chr14-77597351-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 314680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77597351-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.56 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00961 (1464/152346) while in subpopulation AFR AF= 0.0336 (1396/41578). AF 95% confidence interval is 0.0321. There are 22 homozygotes in gnomad4. There are 711 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1464 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPTLC2	NM_004863.4	c.162A>C	p.Leu54Leu	synonymous_variant	2/12	ENST00000216484.7	NP_004854.1
SPTLC2	XM_011537384.3	c.162A>C	p.Leu54Leu	synonymous_variant	2/10		XP_011535686.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPTLC2	ENST00000216484.7	c.162A>C	p.Leu54Leu	synonymous_variant	2/12	1	NM_004863.4	ENSP00000216484.2
SPTLC2	ENST00000557566.1	n.1A>C		non_coding_transcript_exon_variant	1/2	2
SPTLC2	ENST00000554901.1	c.-31A>C		upstream_gene_variant		1		ENSP00000452189.1

Frequencies

GnomAD3 genomes AF: 0.00962 AC: 1465 AN: 152228 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.0337

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00261 AC: 655 AN: 251426 Hom.: 12 AF XY: 0.00210 AC XY: 285 AN XY: 135894

Gnomad AFR exome AF: 0.0351

Gnomad AMR exome AF: 0.00165

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00104 AC: 1521 AN: 1461812 Hom.: 26 Cov.: 31 AF XY: 0.000924 AC XY: 672 AN XY: 727214

Gnomad4 AFR exome AF: 0.0348

Gnomad4 AMR exome AF: 0.00179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.00224

GnomAD4 genome AF: 0.00961 AC: 1464 AN: 152346 Hom.: 22 Cov.: 33 AF XY: 0.00954 AC XY: 711 AN XY: 74506

Gnomad4 AFR AF: 0.0336

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00348 Hom.: 3

Bravo AF: 0.0117

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 05, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

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	-0.59
CADD	Benign	1.1
DANN	Benign	0.67

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: rs115191009; hg19: chr14-78063694;