NM_001267550.2:c.11311+5468G>A

Variant names:

• chr2-178747656-C-T
• rs72648907
• NM_001267550.2:c.11311+5468G>A

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.11311+5468G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 1,613,178 control chromosomes in the GnomAD database, including 2,243 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (146 hom., cov: 32)
  • Exomes 𝑓: 0.050 (2097 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.17
• Publications: 12 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 (MetaRNN=0.0017179251).
• BP6: Variant 2-178747656-C-T is Benign according to our data. Variant chr2-178747656-C-T is described in ClinVar as Benign. ClinVar VariationId is 47775.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0534 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.11311+5468G>A		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.14744G>A	p.Arg4915His	missense	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10360+5468G>A		intron	N/A	NP_001243779.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+5468G>A		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11311+5468G>A		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11035+5468G>A		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0344 AC: 5229 AN: 151982 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0297

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0549

Gnomad OTH AF: 0.0417

GnomAD2 exomes AF: 0.0350 AC: 8746 AN: 250138 AF XY: 0.0351

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.0209

Gnomad ASJ exome AF: 0.0253

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0374

Gnomad NFE exome AF: 0.0577

Gnomad OTH exome AF: 0.0366

GnomAD4 exome AF: 0.0499 AC: 72908 AN: 1461078 Hom.: 2097 Cov.: 35 AF XY: 0.0487 AC XY: 35378 AN XY: 726850

African (AFR) AF: 0.00888 AC: 297 AN: 33436

American (AMR) AF: 0.0215 AC: 959 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 690 AN: 26104

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39664

South Asian (SAS) AF: 0.00256 AC: 221 AN: 86248

European-Finnish (FIN) AF: 0.0388 AC: 2067 AN: 53282

Middle Eastern (MID) AF: 0.0177 AC: 102 AN: 5764

European-Non Finnish (NFE) AF: 0.0595 AC: 66185 AN: 1111596

Other (OTH) AF: 0.0395 AC: 2382 AN: 60354

GnomAD4 genome AF: 0.0344 AC: 5229 AN: 152100 Hom.: 146 Cov.: 32 AF XY: 0.0323 AC XY: 2401 AN XY: 74370

African (AFR) AF: 0.0105 AC: 435 AN: 41516

American (AMR) AF: 0.0297 AC: 453 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.0257 AC: 89 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4828

European-Finnish (FIN) AF: 0.0388 AC: 412 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0549 AC: 3731 AN: 67940

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0445 Hom.: 431

Bravo AF: 0.0330

TwinsUK AF: 0.0628 AC: 233

ALSPAC AF: 0.0669 AC: 258

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.0582 AC: 500

ExAC AF: 0.0358 AC: 4353

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0533

EpiControl AF: 0.0554

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.9
DANN	Benign	0.63
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.00051	N
LIST_S2	Benign	0.34	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Benign	-0.10	N
REVEL	Benign	0.070
Sift	Benign	0.42	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.024
ClinPred		0.016	T
GERP RS		1.8
Mutation Taster		=97/3	polymorphism (auto)

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: rs72648907; hg19: chr2-179612383; COSMIC: COSV107416124; COSMIC: COSV107416124;