14-77570417-C-T

Variant names:

• chr14-77570417-C-T
• rs114519796
• NM_004863.4:c.723G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_004863.4(SPTLC2):​c.723G>A​(p.Thr241Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00149 in 1,613,612 control chromosomes in the GnomAD database, including 36 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 0.0078 (24 hom., cov: 31)
  • Exomes 𝑓: 0.00083 (12 hom.)
• Consequence: SPTLC2 NM_004863.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.28
• Publications: 1 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.249).
• BP6: Variant 14-77570417-C-T is Benign according to our data. Variant chr14-77570417-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 314676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.28 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00782 (1189/152038) while in subpopulation AFR AF = 0.0273 (1133/41450). AF 95% confidence interval is 0.026. There are 24 homozygotes in GnomAd4. There are 544 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1189 AD gene.

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.723G>A	p.Thr241Thr	synonymous	Exon 5 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.723G>A	p.Thr241Thr	synonymous	Exon 5 of 12	ENSP00000216484.2
	SPTLC2	ENST00000554901.1	TSL:1	c.531G>A	p.Thr177Thr	synonymous	Exon 4 of 9	ENSP00000452189.1
	SPTLC2	ENST00000686959.1		n.1454G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00781 AC: 1187 AN: 151920 Hom.: 24 Cov.: 31

Gnomad AFR AF: 0.0273

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00577

GnomAD2 exomes AF: 0.00219 AC: 551 AN: 251318 AF XY: 0.00152

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000829 AC: 1211 AN: 1461574 Hom.: 12 Cov.: 32 AF XY: 0.000714 AC XY: 519 AN XY: 727102

African (AFR) AF: 0.0249 AC: 833 AN: 33476

American (AMR) AF: 0.00266 AC: 119 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86246

European-Finnish (FIN) AF: 0.0000376 AC: 2 AN: 53190

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.000113 AC: 126 AN: 1111970

Other (OTH) AF: 0.00192 AC: 116 AN: 60390

GnomAD4 genome AF: 0.00782 AC: 1189 AN: 152038 Hom.: 24 Cov.: 31 AF XY: 0.00732 AC XY: 544 AN XY: 74306

African (AFR) AF: 0.0273 AC: 1133 AN: 41450

American (AMR) AF: 0.00256 AC: 39 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68002

Other (OTH) AF: 0.00571 AC: 12 AN: 2102

Alfa AF: 0.0000541 Hom.: 9

Bravo AF: 0.00886

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
CADD	Benign	12
DANN	Benign	0.57
PhyloP100		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	polymorphism

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: rs114519796; hg19: chr14-78036760;