chr2-178751160-T-C

Variant names:

• chr2-178751160-T-C
• rs922984
• NM_001267550.2:c.11311+1964A>G

Variant summary

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

The NM_133379.5(TTN):​c.11240A>G​(p.Asp3747Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.887 in 1,611,982 control chromosomes in the GnomAD database, including 641,992 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.80 (50605 hom., cov: 32)
  • Exomes 𝑓: 0.90 (591387 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.57
• Publications: 30 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=8.624961E-7).
• BP6: Variant 2-178751160-T-C is Benign according to our data. Variant chr2-178751160-T-C is described in ClinVar as Benign. ClinVar VariationId is 47736.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.923 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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+1964A>G		intron	N/A	NP_001254479.2
	TTN	NM_133379.5		c.11240A>G	p.Asp3747Gly	missense	Exon 46 of 46	NP_596870.2
	TTN	NM_001256850.1		c.10360+1964A>G		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+1964A>G		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.11311+1964A>G		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.11035+1964A>G		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.804 AC: 121978 AN: 151706 Hom.: 50610 Cov.: 32

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.691

Gnomad ASJ AF: 0.897

Gnomad EAS AF: 0.781

Gnomad SAS AF: 0.789

Gnomad FIN AF: 0.892

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.929

Gnomad OTH AF: 0.840

GnomAD2 exomes AF: 0.820 AC: 203968 AN: 248730 AF XY: 0.836

Gnomad AFR exome AF: 0.599

Gnomad AMR exome AF: 0.558

Gnomad ASJ exome AF: 0.891

Gnomad EAS exome AF: 0.756

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.929

Gnomad OTH exome AF: 0.858

GnomAD4 exome AF: 0.895 AC: 1307511 AN: 1460158 Hom.: 591387 Cov.: 55 AF XY: 0.895 AC XY: 650284 AN XY: 726312

African (AFR) AF: 0.592 AC: 19779 AN: 33416

American (AMR) AF: 0.570 AC: 25427 AN: 44572

Ashkenazi Jewish (ASJ) AF: 0.893 AC: 23261 AN: 26040

East Asian (EAS) AF: 0.783 AC: 31020 AN: 39594

South Asian (SAS) AF: 0.796 AC: 68491 AN: 86078

European-Finnish (FIN) AF: 0.889 AC: 47344 AN: 53264

Middle Eastern (MID) AF: 0.915 AC: 5257 AN: 5748

European-Non Finnish (NFE) AF: 0.931 AC: 1034005 AN: 1111160

Other (OTH) AF: 0.878 AC: 52927 AN: 60286

GnomAD4 genome AF: 0.804 AC: 121992 AN: 151824 Hom.: 50605 Cov.: 32 AF XY: 0.799 AC XY: 59277 AN XY: 74196

African (AFR) AF: 0.606 AC: 25107 AN: 41400

American (AMR) AF: 0.690 AC: 10497 AN: 15204

Ashkenazi Jewish (ASJ) AF: 0.897 AC: 3112 AN: 3470

East Asian (EAS) AF: 0.780 AC: 4016 AN: 5148

South Asian (SAS) AF: 0.790 AC: 3807 AN: 4822

European-Finnish (FIN) AF: 0.892 AC: 9437 AN: 10578

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.929 AC: 63100 AN: 67886

Other (OTH) AF: 0.842 AC: 1779 AN: 2112

Alfa AF: 0.893 Hom.: 226735

Bravo AF: 0.776

TwinsUK AF: 0.931 AC: 3452

ALSPAC AF: 0.928 AC: 3577

ESP6500AA AF: 0.599 AC: 2636

ESP6500EA AF: 0.930 AC: 7989

ExAC AF: 0.826 AC: 100271

Asia WGS AF: 0.782 AC: 2721 AN: 3478

EpiCase AF: 0.934

EpiControl AF: 0.930

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Uncertain	0.99
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	8.6e-7	T
MetaSVM	Benign	-0.94	T
PhyloP100		1.6
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.20
ClinPred		0.0091	T
GERP RS		4.5
Mutation Taster		=91/9	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: rs922984; hg19: chr2-179615887; COSMIC: COSV60071984; COSMIC: COSV60071984;