17-64003872-G-C

Variant names:

• chr17-64003872-G-C
• rs770462917
• NM_001099789.2:c.421C>G

Variant summary

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

The NM_001099789.2(ICAM2):​c.421C>G​(p.Pro141Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ICAM2 NM_001099789.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ICAM2	NM_001099789.2	c.421C>G	p.Pro141Ala	missense_variant	Exon 4 of 5	ENST00000579788.6	NP_001093259.1
PRR29	NM_001164257.2	c.*2111G>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.421C>G	p.Pro141Ala	missense_variant	Exon 4 of 5	1	NM_001099789.2	ENSP00000464665.1
PRR29	ENST00000412177.6	c.*2111G>C		3_prime_UTR_variant	Exon 6 of 6	2	NM_001164257.2	ENSP00000400986.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461854 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000329 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 24, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.421C>G (p.P141A) alteration is located in exon 5 (coding exon 3) of the ICAM2 gene. This alteration results from a C to G substitution at nucleotide position 421, causing the proline (P) at amino acid position 141 to be replaced by an alanine (A). 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	Pathogenic	0.70
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.48	.;T;D;D;D;D;D;T;T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.77	T;T;.;.;.;T;.;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.8	.;.;M;M;M;M;M;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-7.4	.;.;D;.;D;D;.;.;.;.
REVEL	Benign	0.16
Sift	Benign	0.039	.;.;D;.;D;D;.;.;.;.
Sift4G	Benign	0.19	T;T;T;T;T;T;T;.;.;.
Polyphen		0.98	.;.;D;D;D;D;D;.;.;.
Vest4		0.52
MutPred		0.65		.;.;Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);Loss of glycosylation at T138 (P = 0.0735);
MVP		0.66
MPC		0.74
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.51
gMVP		0.55

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: rs770462917; hg19: chr17-62081232;