11-124924861-ACG-CCC

Variant names:

• chr11-124924861-ACG-CCC
• NM_152722.5:c.292_294delCGTinsGGG
• HEPACAM p.Arg98Gly

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_152722.5(HEPACAM):​c.292_294delCGTinsGGG​(p.Arg98Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R98H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HEPACAM NM_152722.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.99
• Publications: 0 publications found

Genes affected

HEPACAM (HGNC:26361): (hepatic and glial cell adhesion molecule) The protein encoded by this gene is a single-pass type I membrane protein that localizes to the cytoplasmic side of the cell membrane. The encoded protein acts as a homodimer and is involved in cell motility and cell-matrix interactions. The expression of this gene is downregulated or undetectable in many cancer cell lines, so this may be a tumor suppressor gene. [provided by RefSeq, Jul 2011]

HEPACAM Gene-Disease associations (from GenCC):

• megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with or without intellectual disability

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• megalencephalic leukoencephalopathy with subcortical cysts 2A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• macrocephaly-autism syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• megalencephalic leukoencephalopathy with subcortical cysts

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000254943 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_152722.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-124924863-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 30918.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152722.5. 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
	HEPACAM	NM_152722.5	MANE Select	c.292_294delCGTinsGGG	p.Arg98Gly	missense	N/A	NP_689935.2	Q14CZ8-1
	HEPACAM	NM_001411043.1		c.292_294delCGTinsGGG	p.Arg98Gly	missense	N/A	NP_001397972.1	A0A994J4I1
	HEPACAM	NM_001441320.1		c.292_294delCGTinsGGG	p.Arg98Gly	missense	N/A	NP_001428249.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEPACAM	ENST00000298251.5	TSL:1 MANE Select	c.292_294delCGTinsGGG	p.Arg98Gly	missense	N/A	ENSP00000298251.4	Q14CZ8-1
	HEPACAM	ENST00000872129.1		c.292_294delCGTinsGGG	p.Arg98Gly	missense	N/A	ENSP00000542188.1
	HEPACAM	ENST00000703807.1		c.292_294delCGTinsGGG	p.Arg98Gly	missense	N/A	ENSP00000515485.1	A0A994J4I1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.0

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr11-124794757;