chr14-77570417-C-A

Position:

• chr14-77570417-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004863.4(SPTLC2):​c.723G>T​(p.Thr241=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0026 in 1,613,606 control chromosomes in the GnomAD database, including 113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T241T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.014 (66 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (47 hom.)
• Consequence: SPTLC2 NM_004863.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.28

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.21).
• BP6: Variant 14-77570417-C-A is Benign according to our data. Variant chr14-77570417-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 314675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-77570417-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0139 (2106/152032) while in subpopulation AFR AF= 0.0479 (1983/41442). AF 95% confidence interval is 0.0461. There are 66 homozygotes in gnomad4. There are 1002 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2106 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPTLC2	NM_004863.4	c.723G>T	p.Thr241=	synonymous_variant	5/12	ENST00000216484.7
SPTLC2	XM_011537384.3	c.723G>T	p.Thr241=	synonymous_variant	5/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPTLC2	ENST00000216484.7	c.723G>T	p.Thr241=	synonymous_variant	5/12	1	NM_004863.4	P1

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 2097 AN: 151914 Hom.: 65 Cov.: 31

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00552

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00364 AC: 914 AN: 251318 Hom.: 18 AF XY: 0.00268 AC XY: 364 AN XY: 135840

Gnomad AFR exome AF: 0.0489

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.00143 AC: 2092 AN: 1461574 Hom.: 47 Cov.: 32 AF XY: 0.00124 AC XY: 902 AN XY: 727102

Gnomad4 AFR exome AF: 0.0494

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000647

Gnomad4 OTH exome AF: 0.00306

GnomAD4 genome AF: 0.0139 AC: 2106 AN: 152032 Hom.: 66 Cov.: 31 AF XY: 0.0135 AC XY: 1002 AN XY: 74304

Gnomad4 AFR AF: 0.0478

Gnomad4 AMR AF: 0.00551

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.0143

Alfa AF: 0.00160 Hom.: 4

Bravo AF: 0.0162

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

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	Sep 21, 2023	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 08, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not provided Benign:2

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.21
CADD	Benign	8.1
DANN	Benign	0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs114519796; hg19: chr14-78036760;