17-64003947-T-G

Variant names:

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

Variant summary

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

The NM_001099789.2(ICAM2):​c.346A>C​(p.Ile116Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. I116V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ICAM2 NM_001099789.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.612
• Publications: 0 publications found

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

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=0.07068512).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099789.2. 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
	ICAM2	NM_001099789.2	MANE Select	c.346A>C	p.Ile116Leu	missense	Exon 4 of 5	NP_001093259.1	Q6FHE2
	PRR29	NM_001164257.2	MANE Select	c.*2186T>G		3_prime_UTR	Exon 6 of 6	NP_001157729.1	P0C7W0-1
	ICAM2	NM_000873.4		c.346A>C	p.Ile116Leu	missense	Exon 3 of 4	NP_000864.2	Q6FHE2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ICAM2	ENST00000579788.6	TSL:1 MANE Select	c.346A>C	p.Ile116Leu	missense	Exon 4 of 5	ENSP00000464665.1	P13598
	ICAM2	ENST00000449662.6	TSL:1	c.346A>C	p.Ile116Leu	missense	Exon 3 of 4	ENSP00000392634.2	P13598
	PRR29	ENST00000412177.6	TSL:2 MANE Select	c.*2186T>G		3_prime_UTR	Exon 6 of 6	ENSP00000400986.1	P0C7W0-1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460308 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726402

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

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111366

Other (OTH) AF: 0.00 AC: 0 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.11
DANN	Benign	0.36
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.45	N
PhyloP100		-0.61
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.080	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.074
MutPred		0.49		Loss of sheet (P = 0.1158)
MVP		0.055
MPC		0.26
ClinPred		0.043	T
GERP RS		-0.63
Varity_R		0.084
gMVP		0.17

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: rs1251742846; hg19: chr17-62081307;