2-130152705-C-CCGGTAACTGCCCAGGAAG

Variant names:

• chr2-130152705-C-CCGGTAACTGCCCAGGAAG
• NM_017951.5:c.2316_2333dupCTTCCTGGGCAGTTACCG

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4

The NM_017951.5(SMPD4):​c.2316_2333dupCTTCCTGGGCAGTTACCG​(p.Arg778_Thr779insPheLeuGlySerTyrArg) variant causes a disruptive inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMPD4 NM_017951.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.14

Genes affected

SMPD4 (HGNC:32949): (sphingomyelin phosphodiesterase 4) The protein encoded by this gene is a sphingomyelinase that catalyzes the hydrolysis of membrane sphingomyelin to form phosphorylcholine and ceramide. This gene is activated by DNA damage, cellular stress, and tumor necrosis factor, but it is downregulated by wild-type p53. The encoded protein localizes to the endoplasmic reticulum and Golgi network. [provided by RefSeq, Mar 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_017951.5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMPD4	NM_017951.5	c.2316_2333dupCTTCCTGGGCAGTTACCG	p.Arg778_Thr779insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 20 of 20	ENST00000680298.1	NP_060421.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMPD4	ENST00000680298.1	c.2316_2333dupCTTCCTGGGCAGTTACCG	p.Arg778_Thr779insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 20 of 20		NM_017951.5	ENSP00000506463.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies Uncertain:2

Aug 21, 2023

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 21, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame duplication of 6 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-130910278;