chr14-77562460-A-G

Variant names:

• chr14-77562460-A-G
• rs2364602
• NM_004863.4:c.786T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate 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
• Publications: 23 publications found

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 Gene-Disease associations (from GenCC):

• neuropathy, hereditary sensory and autonomic, type 1C

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Ambry Genetics
• hereditary sensory and autonomic neuropathy type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.067).
• BP6: Variant 14-77562460-A-G is Benign according to our data. Variant chr14-77562460-A-G is described in ClinVar as Benign. ClinVar VariationId is 314672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004863.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC2	NM_004863.4	MANE Select	c.786T>C	p.Asn262Asn	synonymous	Exon 6 of 12	NP_004854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPTLC2	ENST00000216484.7	TSL:1 MANE Select	c.786T>C	p.Asn262Asn	synonymous	Exon 6 of 12	ENSP00000216484.2
	SPTLC2	ENST00000554901.1	TSL:1	c.594T>C	p.Asn198Asn	synonymous	Exon 5 of 9	ENSP00000452189.1
	SPTLC2	ENST00000687688.1		n.549T>C		non_coding_transcript_exon	Exon 3 of 9

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

GnomAD2 exomes AF: 0.904 AC: 227343 AN: 251412 AF XY: 0.916

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 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

African (AFR) AF: 0.606 AC: 20292 AN: 33468

American (AMR) AF: 0.801 AC: 35834 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.959 AC: 25054 AN: 26128

East Asian (EAS) AF: 0.996 AC: 39534 AN: 39690

South Asian (SAS) AF: 0.965 AC: 83197 AN: 86258

European-Finnish (FIN) AF: 0.943 AC: 50390 AN: 53414

Middle Eastern (MID) AF: 0.939 AC: 5415 AN: 5768

European-Non Finnish (NFE) AF: 0.932 AC: 1035829 AN: 1111876

Other (OTH) AF: 0.922 AC: 55698 AN: 60384

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

African (AFR) AF: 0.622 AC: 25790 AN: 41462

American (AMR) AF: 0.823 AC: 12588 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.960 AC: 3333 AN: 3472

East Asian (EAS) AF: 0.990 AC: 5124 AN: 5178

South Asian (SAS) AF: 0.960 AC: 4639 AN: 4830

European-Finnish (FIN) AF: 0.944 AC: 10026 AN: 10618

Middle Eastern (MID) AF: 0.966 AC: 284 AN: 294

European-Non Finnish (NFE) AF: 0.934 AC: 63545 AN: 68026

Other (OTH) AF: 0.878 AC: 1854 AN: 2112

Alfa AF: 0.918 Hom.: 114809

Bravo AF: 0.825

Asia WGS AF: 0.952 AC: 3311 AN: 3478

EpiCase AF: 0.937

EpiControl AF: 0.936

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Neuropathy, hereditary sensory and autonomic, type 1C (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	11
DANN	Benign	0.62
PhyloP100		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism (auto)

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: rs2364602; hg19: chr14-78028803; COSMIC: COSV108036308;