5-115581066-C-A

Variant names:

• chr5-115581066-C-A
• rs113049216
• NM_021649.7:c.191G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021649.7(TICAM2):​c.191G>T​(p.Ser64Ile) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TICAM2 NM_021649.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.60

Genes affected

TICAM2 (HGNC:21354): (TIR domain containing adaptor molecule 2) Predicted to enable phospholipid binding activity. Involved in several processes, including TRAM-dependent toll-like receptor 4 signaling pathway; regulation of chemokine (C-C motif) ligand 5 production; and regulation of toll-like receptor 4 signaling pathway. Located in endoplasmic reticulum; endosome; and phagocytic cup. [provided by Alliance of Genome Resources, Apr 2022]

TMED7-TICAM2 (HGNC:33945): (TMED7-TICAM2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring transmembrane emp24 protein transport domain containing 7 (TMED7) and toll-like receptor adaptor molecule 2 (TICAM2) genes. Alternative splicing results in multiple transcript variants, one of which encodes a fusion protein that shares sequence identity with the products of each individual gene. This fusion product functions to negatively regulate the adaptor MyD88-independent toll-like receptor 4 pathway. [provided by RefSeq, Nov 2010]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06493354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICAM2	NM_021649.7	c.191G>T	p.Ser64Ile	missense_variant	Exon 2 of 2	ENST00000427199.3	NP_067681.1
TMED7-TICAM2	NM_001164468.4	c.698G>T	p.Ser233Ile	missense_variant	Exon 4 of 4		NP_001157940.1
TMED7-TICAM2	NM_001164469.4	c.*249G>T		3_prime_UTR_variant	Exon 4 of 4		NP_001157941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TICAM2	ENST00000427199.3	c.191G>T	p.Ser64Ile	missense_variant	Exon 2 of 2	1	NM_021649.7	ENSP00000415139.3
TMED7-TICAM2	ENST00000282382.8	c.698G>T	p.Ser233Ile	missense_variant	Exon 4 of 4	2		ENSP00000282382.4
TMED7-TICAM2	ENST00000333314	c.*249G>T		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000333650.3
TMED7-TICAM2	ENST00000514548.1	n.497G>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.33
DANN	Benign	0.96
DEOGEN2	Benign	0.087	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.34	T;T
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.065	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.0090
Sift	Benign	0.051	T;T
Sift4G	Benign	0.075	T;T
Polyphen		0.0050	.;B
Vest4		0.078
MutPred		0.28		.;Loss of phosphorylation at S64 (P = 0.012);
MVP		0.12
MPC		0.99
ClinPred		0.13	T
GERP RS		-0.31
Varity_R		0.043
gMVP		0.32

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: rs113049216; hg19: chr5-114916763;