NM_030926.6:c.667A>C

Variant names:

• chr2-230877505-A-C
• rs766463695
• NM_030926.6:c.667A>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030926.6(ITM2C):​c.667A>C​(p.Asn223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ITM2C NM_030926.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09174782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ITM2C	NM_030926.6	c.667A>C	p.Asn223His	missense_variant	Exon 5 of 6	ENST00000326427.11	NP_112188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ITM2C	ENST00000326427.11	c.667A>C	p.Asn223His	missense_variant	Exon 5 of 6	1	NM_030926.6	ENSP00000322730.6
ITM2C	ENST00000326407.10	c.556A>C	p.Asn186His	missense_variant	Exon 4 of 5	1		ENSP00000322100.6
ITM2C	ENST00000335005.10	c.526A>C	p.Asn176His	missense_variant	Exon 4 of 5	1		ENSP00000335121.6
ITM2C	ENST00000409704.6	c.481A>C	p.Asn161His	missense_variant	Exon 5 of 6	5		ENSP00000387242.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251342 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135878

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461716 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727174

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	17
DANN	Benign	0.23
DEOGEN2	Benign	0.013	T;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.74	T;D;T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.092	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N;.;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.93	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.85	T;T;T;T
Sift4G	Benign	0.69	T;T;T;T
Polyphen		0.0090	B;B;B;.
Vest4		0.29
MutPred		0.32		Loss of MoRF binding (P = 0.1083);.;.;.;
MVP		0.74
MPC		0.25
ClinPred		0.051	T
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.062
gMVP		0.46

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

LitVar

Other links and lift over

dbSNP: rs766463695; hg19: chr2-231742220;