chr2-130152705-C-CCGGTAACTGCCCAGGAAG

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. 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. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. 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
• Publications: 0 publications found

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]

SMPD4 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_017951.5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017951.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD4	NM_017951.5	MANE Select	c.2316_2333dupCTTCCTGGGCAGTTACCG	p.Arg778_Thr779insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 20 of 20	NP_060421.3	A0A7P0TB24
	SMPD4	NM_017751.4		c.2346_2363dupCTTCCTGGGCAGTTACCG	p.Arg788_Thr789insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 19 of 19	NP_060221.2	Q9NXE4-2
	SMPD4	NM_001171083.2		c.2127_2144dupCTTCCTGGGCAGTTACCG	p.Arg715_Thr716insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 17 of 17	NP_001164554.1	Q9NXE4-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMPD4	ENST00000680298.1	MANE Select	c.2316_2333dupCTTCCTGGGCAGTTACCG	p.Arg778_Thr779insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 20 of 20	ENSP00000506463.1	A0A7P0TB24
	SMPD4	ENST00000409031.5	TSL:1	c.2433_2450dupCTTCCTGGGCAGTTACCG	p.Arg817_Thr818insPheLeuGlySerTyrArg	disruptive_inframe_insertion	Exon 20 of 20	ENSP00000386531.1	Q9NXE4-1
	SMPD4	ENST00000454468.5	TSL:1	n.*2020_*2037dupCTTCCTGGGCAGTTACCG		non_coding_transcript_exon	Exon 19 of 19	ENSP00000407591.1	F8WF03

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Neurodevelopmental disorder with microcephaly, arthrogryposis, and structural brain anomalies (2)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.1

Splicing

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

Other links and lift over

hg19: chr2-130910278;