NM_001099789.2:c.346A>G

Variant names:

• chr17-64003947-T-C
• rs1251742846
• NM_001099789.2:c.346A>G

Variant summary

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

The NM_001099789.2(ICAM2):​c.346A>G​(p.Ile116Val) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ICAM2 NM_001099789.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.612

Genes affected

ICAM2 (HGNC:5345): (intercellular adhesion molecule 2) The protein encoded by this gene is a member of the intercellular adhesion molecule (ICAM) family. All ICAM proteins are type I transmembrane glycoproteins, contain 2-9 immunoglobulin-like C2-type domains, and bind to the leukocyte adhesion LFA-1 protein. This protein may play a role in lymphocyte recirculation by blocking LFA-1-dependent cell adhesion. It mediates adhesive interactions important for antigen-specific immune response, NK-cell mediated clearance, lymphocyte recirculation, and other cellular interactions important for immune response and surveillance. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jul 2008]

PRR29 (HGNC:25673): (proline rich 29)

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=0.08560616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM2	NM_001099789.2	c.346A>G	p.Ile116Val	missense_variant	Exon 4 of 5	ENST00000579788.6	NP_001093259.1
PRR29	NM_001164257.2	c.*2186T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000412177.6	NP_001157729.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ICAM2	ENST00000579788.6	c.346A>G	p.Ile116Val	missense_variant	Exon 4 of 5	1	NM_001099789.2	ENSP00000464665.1
PRR29	ENST00000412177.6	c.*2186T>C		3_prime_UTR_variant	Exon 6 of 6	2	NM_001164257.2	ENSP00000400986.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000406 AC: 1 AN: 246248 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133232

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

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 Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346A>G (p.I116V) alteration is located in exon 5 (coding exon 3) of the ICAM2 gene. This alteration results from a A to G substitution at nucleotide position 346, causing the isoleucine (I) at amino acid position 116 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.45
DANN	Benign	0.34
DEOGEN2	Benign	0.0097	.;T;T;T;T;T;T;T;T;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.56	T;T;.;.;.;T;.;T;T;T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.99	.;.;L;L;L;L;L;.;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	0.16	.;.;N;.;N;N;.;.;.;.
REVEL	Benign	0.020
Sift	Benign	0.61	.;.;T;.;T;T;.;.;.;.
Sift4G	Benign	1.0	T;T;T;T;T;T;T;.;.;.
Polyphen		0.0	.;.;B;B;B;B;B;.;.;.
Vest4		0.033
MutPred		0.49		.;.;Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);Gain of catalytic residue at I116 (P = 0.1863);
MVP		0.072
MPC		0.22
ClinPred		0.023	T
GERP RS		-0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.044
gMVP		0.10

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: rs1251742846; hg19: chr17-62081307;