rs16866373

Variant names:

• chr2-178527353-A-T
• rs16866373
• NM_001267550.2:c.107681-46T>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178527353-A-T
• chr2-178527353-A-C
• chr2-178527353-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.107681-46T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,561,934 control chromosomes in the GnomAD database, including 21,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1984 hom., cov: 33)
  • Exomes 𝑓: 0.15 (19228 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.62
• Publications: 7 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-178527353-A-T is Benign according to our data. Variant chr2-178527353-A-T is described in ClinVar as Benign. ClinVar VariationId is 262345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.107681-46T>A		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.102758-46T>A		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.99977-46T>A		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.107681-46T>A		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.107525-46T>A		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.107405-46T>A		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21595 AN: 152132 Hom.: 1978 Cov.: 33

Gnomad AFR AF: 0.0758

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.129

Gnomad ASJ AF: 0.171

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.127

GnomAD2 exomes AF: 0.176 AC: 36754 AN: 208668 AF XY: 0.179

Gnomad AFR exome AF: 0.0707

Gnomad AMR exome AF: 0.149

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.432

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.144

Gnomad OTH exome AF: 0.162

GnomAD4 exome AF: 0.154 AC: 216709 AN: 1409684 Hom.: 19228 Cov.: 32 AF XY: 0.156 AC XY: 108848 AN XY: 696076

African (AFR) AF: 0.0717 AC: 2241 AN: 31260

American (AMR) AF: 0.148 AC: 5394 AN: 36436

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 3853 AN: 22974

East Asian (EAS) AF: 0.435 AC: 17048 AN: 39208

South Asian (SAS) AF: 0.252 AC: 19448 AN: 77158

European-Finnish (FIN) AF: 0.151 AC: 7731 AN: 51168

Middle Eastern (MID) AF: 0.125 AC: 688 AN: 5484

European-Non Finnish (NFE) AF: 0.139 AC: 150898 AN: 1088034

Other (OTH) AF: 0.162 AC: 9408 AN: 57962

GnomAD4 genome AF: 0.142 AC: 21605 AN: 152250 Hom.: 1984 Cov.: 33 AF XY: 0.147 AC XY: 10919 AN XY: 74442

African (AFR) AF: 0.0756 AC: 3143 AN: 41566

American (AMR) AF: 0.128 AC: 1963 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 592 AN: 3470

East Asian (EAS) AF: 0.443 AC: 2293 AN: 5180

South Asian (SAS) AF: 0.256 AC: 1234 AN: 4822

European-Finnish (FIN) AF: 0.162 AC: 1717 AN: 10602

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9907 AN: 67994

Other (OTH) AF: 0.136 AC: 288 AN: 2114

Alfa AF: 0.0976 Hom.: 214

Bravo AF: 0.137

Asia WGS AF: 0.341 AC: 1186 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not specified (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.7
DANN	Benign	0.59
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs16866373; hg19: chr2-179392080; COSMIC: COSV59894482; COSMIC: COSV59894482;