Genetic Variant SPTLC2:p.Ala41_Ala42dup (chr14-77616452-C-CCGGCGG) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP3BP6BS2

The NM_004863.4(SPTLC2):c.122_127dupCCGCCG(p.Ala41_Ala42dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,484,176 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

SPTLC2
NM_004863.4 conservative_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.0210

Publications

0 publications found

Variant links:

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

SPTLC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_004863.4

BP6

Variant 14-77616452-C-CCGGCGG is Benign according to our data. Variant chr14-77616452-C-CCGGCGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 538849.

BS2

High AC in GnomAdExome4 at 22 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.122_127dupCCGCCG	p.Ala41_Ala42dup	conservative_inframe_insertion	Exon 1 of 12	NP_004854.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SPTLC2	ENST00000216484.7	TSL:1 MANE Select	c.122_127dupCCGCCG	p.Ala41_Ala42dup	conservative_inframe_insertion	Exon 1 of 12	ENSP00000216484.2
SPTLC2	ENST00000950640.1		c.122_127dupCCGCCG	p.Ala41_Ala42dup	conservative_inframe_insertion	Exon 1 of 13	ENSP00000620699.1
SPTLC2	ENST00000950639.1		c.122_127dupCCGCCG	p.Ala41_Ala42dup	conservative_inframe_insertion	Exon 1 of 13	ENSP00000620698.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000165

AC:

AN:

1332070

Hom.:

Cov.:

AF XY:

0.0000259

AC XY:

AN XY:

656592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26888

American (AMR)

AF:

0.00

AC:

AN:

29724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23300

East Asian (EAS)

AF:

0.00

AC:

AN:

29512

South Asian (SAS)

AF:

0.0000135

AC:

AN:

74246

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5028

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1054786

Other (OTH)

AF:

0.00

AC:

AN:

55378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74374

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000241

AC:

AN:

41548

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10560

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2108

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Neuropathy, hereditary sensory and autonomic, type 1C (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.021

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over