NM_021649.7:c.271G>C

Variant names:

• chr5-115580986-C-G
• rs760570311
• NM_021649.7:c.271G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021649.7(TICAM2):​c.271G>C​(p.Asp91His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,476 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TICAM2 NM_021649.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032554477).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021649.7. 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
	TICAM2	NM_021649.7	MANE Select	c.271G>C	p.Asp91His	missense	Exon 2 of 2	NP_067681.1	Q86XR7-1
	TMED7-TICAM2	NM_001164468.4		c.778G>C	p.Asp260His	missense	Exon 4 of 4	NP_001157940.1
	TMED7-TICAM2	NM_001164469.4		c.*329G>C		3_prime_UTR	Exon 4 of 4	NP_001157941.1	A0A0A6YYA0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM2	ENST00000427199.3	TSL:1 MANE Select	c.271G>C	p.Asp91His	missense	Exon 2 of 2	ENSP00000415139.3	Q86XR7-1
	TMED7-TICAM2	ENST00000282382.8	TSL:2	c.778G>C	p.Asp260His	missense	Exon 4 of 4	ENSP00000282382.4
	TICAM2	ENST00000957908.1		c.271G>C	p.Asp91His	missense	Exon 2 of 2	ENSP00000627967.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000805 AC: 2 AN: 248416 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461476 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727038

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111844

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.077	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0035	T
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.58
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.043
Sift	Benign	0.058	T
Sift4G	Benign	0.23	T
Polyphen		0.0030	B
Vest4		0.18
MutPred		0.14		Gain of sheet (P = 0.0827)
MVP		0.061
MPC		0.014
ClinPred		0.033	T
GERP RS		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.44
Mutation Taster		=87/13	polymorphism

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: rs760570311; hg19: chr5-114916683;