Genetic Variant ITM2C:p.Phe74Leu (chr2-230873516-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030926.6(ITM2C):c.220T>C(p.Phe74Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,640 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. F74I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ITM2C
NM_030926.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.01

Publications

0 publications found

Variant links:

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]

ITM2C links:

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ACMG classification

Classification was made for transcript

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=0.07722303).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITM2C	NM_030926.6	MANE Select	c.220T>C	p.Phe74Leu	missense	Exon 2 of 6	NP_112188.1	Q9NQX7-1
ITM2C	NM_001287241.2		c.220T>C	p.Phe74Leu	missense	Exon 3 of 7	NP_001274170.1	Q9NQX7-1
ITM2C	NM_001012516.2		c.220T>C	p.Phe74Leu	missense	Exon 2 of 5	NP_001012534.1	Q9NQX7-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ITM2C	ENST00000326427.11	TSL:1 MANE Select	c.220T>C	p.Phe74Leu	missense	Exon 2 of 6	ENSP00000322730.6	Q9NQX7-1
ITM2C	ENST00000326407.10	TSL:1	c.220T>C	p.Phe74Leu	missense	Exon 2 of 5	ENSP00000322100.6	Q9NQX7-3
ITM2C	ENST00000335005.10	TSL:1	c.121-2104T>C		intron	N/A	ENSP00000335121.6	Q9NQX7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000404

AC:

AN:

247718

AF XY:

0.00

show subpopulations

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458640

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33370

American (AMR)

AF:

0.00

AC:

AN:

44224

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26062

East Asian (EAS)

AF:

0.00

AC:

AN:

39462

South Asian (SAS)

AF:

0.00

AC:

AN:

85494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110706

Other (OTH)

AF:

0.00

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0053

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0065

MetaRNN

Benign

0.077

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.080

PhyloP100

2.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

1.1

REVEL

Benign

0.033

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.20

MutPred

0.31

Loss of catalytic residue at F74 (P = 0.1062)

MVP

0.26

MPC

0.28

ClinPred

0.39

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.070

gMVP

0.68

Mutation Taster

=82/18

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over