5-115580654-T-G

Position:

• chr5-115580654-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_021649.7(TICAM2):​c.603A>C​(p.Gly201Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,581,164 control chromosomes in the GnomAD database, including 51 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: TICAM2 NM_021649.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.95

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 5-115580654-T-G is Benign according to our data. Variant chr5-115580654-T-G is described in ClinVar as [Benign]. Clinvar id is 790566.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.95 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1534/152270) while in subpopulation AFR AF= 0.0354 (1472/41534). AF 95% confidence interval is 0.0339. There are 28 homozygotes in gnomad4. There are 709 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICAM2	NM_021649.7	c.603A>C	p.Gly201Gly	synonymous_variant	2/2	ENST00000427199.3	NP_067681.1
TMED7-TICAM2	NM_001164468.4	c.1110A>C	p.Gly370Gly	synonymous_variant	4/4		NP_001157940.1
TMED7-TICAM2	NM_001164469.4	c.*661A>C		3_prime_UTR_variant	4/4		NP_001157941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM2	ENST00000427199.3	c.603A>C	p.Gly201Gly	synonymous_variant	2/2	1	NM_021649.7	ENSP00000415139.3
TMED7-TICAM2	ENST00000282382.8	c.1110A>C	p.Gly370Gly	synonymous_variant	4/4	2		ENSP00000282382.4
TMED7-TICAM2	ENST00000333314.3	c.*661A>C		3_prime_UTR_variant	4/4	2		ENSP00000333650.3

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1533 AN: 152152 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00717

GnomAD3 exomes AF: 0.00306 AC: 657 AN: 214572 Hom.: 7 AF XY: 0.00235 AC XY: 272 AN XY: 115590

Gnomad AFR exome AF: 0.0366

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000875

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000190

Gnomad OTH exome AF: 0.000797

GnomAD4 exome AF: 0.00107 AC: 1536 AN: 1428894 Hom.: 23 Cov.: 31 AF XY: 0.000957 AC XY: 679 AN XY: 709522

Gnomad4 AFR exome AF: 0.0367

Gnomad4 AMR exome AF: 0.00194

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000754

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000125

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.0101 AC: 1534 AN: 152270 Hom.: 28 Cov.: 32 AF XY: 0.00952 AC XY: 709 AN XY: 74472

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00637 Hom.: 2

Bravo AF: 0.0114

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	9.3
DANN	Benign	0.71

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: rs7705473; hg19: chr5-114916351;