2-230875627-G-C

Variant names:

• chr2-230875627-G-C
• rs760132646
• NM_030926.6:c.269G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_030926.6(ITM2C):​c.269G>C​(p.Arg90Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. R90Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ITM2C NM_030926.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.22
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39845762).

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.269G>C	p.Arg90Pro	missense	Exon 3 of 6	NP_112188.1	Q9NQX7-1
	ITM2C	NM_001287241.2		c.269G>C	p.Arg90Pro	missense	Exon 4 of 7	NP_001274170.1	Q9NQX7-1
	ITM2C	NM_001012516.2		c.269G>C	p.Arg90Pro	missense	Exon 3 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.269G>C	p.Arg90Pro	missense	Exon 3 of 6	ENSP00000322730.6	Q9NQX7-1
	ITM2C	ENST00000326407.10	TSL:1	c.269G>C	p.Arg90Pro	missense	Exon 3 of 5	ENSP00000322100.6	Q9NQX7-3
	ITM2C	ENST00000335005.10	TSL:1	c.128G>C	p.Arg43Pro	missense	Exon 2 of 5	ENSP00000335121.6	Q9NQX7-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.3	L
PhyloP100		3.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Benign	0.37	T
Sift4G	Benign	0.097	T
Polyphen		0.94	P
Vest4		0.89
MutPred		0.45		Loss of solvent accessibility (P = 0.0364)
MVP		0.73
MPC		0.97
ClinPred		0.83	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.35
gMVP		0.93
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760132646; hg19: chr2-231740342;