2-230865108-C-G

Variant names:

• chr2-230865108-C-G
• rs372949270
• NM_030926.6:c.83C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030926.6(ITM2C):​c.83C>G​(p.Pro28Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000133 in 1,507,962 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P28L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: ITM2C NM_030926.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.13
• Publications: 1 publications found

Genes affected

ITM2C (HGNC:6175): (integral membrane protein 2C) Enables amyloid-beta binding activity. Involved in negative regulation of neuron projection development and neuron differentiation. Located in several cellular components, including Golgi apparatus; lysosome; and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000308773 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06901437).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030926.6. 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
	ITM2C	NM_030926.6	MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 6	NP_112188.1	Q9NQX7-1
	ITM2C	NM_001287241.2		c.83C>G	p.Pro28Arg	missense	Exon 2 of 7	NP_001274170.1	Q9NQX7-1
	ITM2C	NM_001012516.2		c.83C>G	p.Pro28Arg	missense	Exon 1 of 5	NP_001012534.1	Q9NQX7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ITM2C	ENST00000326427.11	TSL:1 MANE Select	c.83C>G	p.Pro28Arg	missense	Exon 1 of 6	ENSP00000322730.6	Q9NQX7-1
	ITM2C	ENST00000326407.10	TSL:1	c.83C>G	p.Pro28Arg	missense	Exon 1 of 5	ENSP00000322100.6	Q9NQX7-3
	ITM2C	ENST00000335005.10	TSL:1	c.83C>G	p.Pro28Arg	missense	Exon 1 of 5	ENSP00000335121.6	Q9NQX7-2

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151146 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000756 AC: 1 AN: 132226 AF XY: 0.0000136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000190

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.37e-7 AC: 1 AN: 1356694 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 668460

African (AFR) AF: 0.00 AC: 0 AN: 28734

American (AMR) AF: 0.00 AC: 0 AN: 34246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23706

East Asian (EAS) AF: 0.00 AC: 0 AN: 32176

South Asian (SAS) AF: 0.00 AC: 0 AN: 75216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5506

European-Non Finnish (NFE) AF: 9.48e-7 AC: 1 AN: 1055256

Other (OTH) AF: 0.00 AC: 0 AN: 55538

GnomAD4 genome AF: 0.00000661 AC: 1 AN: 151268 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73890

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

African (AFR) AF: 0.00 AC: 0 AN: 41200

American (AMR) AF: 0.00 AC: 0 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5048

South Asian (SAS) AF: 0.00 AC: 0 AN: 4744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67706

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ 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.

ExAC AF: 0.00000869 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.52
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.63	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.015
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.011	D
Polyphen		0.17	B
Vest4		0.083
MutPred		0.28		Loss of sheet (P = 0.0025)
MVP		0.52
MPC		0.25
ClinPred		0.086	T
GERP RS		1.7
PromoterAI		0.052	Neutral
Varity_R		0.065
gMVP		0.36
Mutation Taster		=95/5	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: rs372949270; hg19: chr2-231729823;