rs4894048

Variant names:

• chr2-178773994-C-T
• rs4894048
• NM_001267550.2:c.7174G>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.7174G>A​(p.Gly2392Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0405 in 1,613,948 control chromosomes in the GnomAD database, including 2,940 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G2392G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.060 (427 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2513 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 4.17
• Publications: 26 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=0.0017631948).
• BP6: Variant 2-178773994-C-T is Benign according to our data. Variant chr2-178773994-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.137 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.7174G>A	p.Gly2392Ser	missense	Exon 31 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.7174G>A	p.Gly2392Ser	missense	Exon 31 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.7174G>A	p.Gly2392Ser	missense	Exon 31 of 312	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.7174G>A	p.Gly2392Ser	missense	Exon 31 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.7174G>A	p.Gly2392Ser	missense	Exon 31 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.6898G>A	p.Gly2300Ser	missense	Exon 29 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0595 AC: 9046 AN: 152024 Hom.: 419 Cov.: 32

Gnomad AFR AF: 0.0920

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.0162

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.0579

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0223

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0700 AC: 17574 AN: 250978 AF XY: 0.0677

Gnomad AFR exome AF: 0.0946

Gnomad AMR exome AF: 0.187

Gnomad ASJ exome AF: 0.0340

Gnomad EAS exome AF: 0.0187

Gnomad FIN exome AF: 0.0561

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0567

GnomAD4 exome AF: 0.0385 AC: 56347 AN: 1461806 Hom.: 2513 Cov.: 34 AF XY: 0.0408 AC XY: 29663 AN XY: 727214

African (AFR) AF: 0.0929 AC: 3109 AN: 33474

American (AMR) AF: 0.184 AC: 8230 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 880 AN: 26136

East Asian (EAS) AF: 0.00942 AC: 374 AN: 39690

South Asian (SAS) AF: 0.147 AC: 12714 AN: 86258

European-Finnish (FIN) AF: 0.0574 AC: 3064 AN: 53420

Middle Eastern (MID) AF: 0.0473 AC: 273 AN: 5768

European-Non Finnish (NFE) AF: 0.0225 AC: 25073 AN: 1111960

Other (OTH) AF: 0.0435 AC: 2630 AN: 60392

GnomAD4 genome AF: 0.0596 AC: 9070 AN: 152142 Hom.: 427 Cov.: 32 AF XY: 0.0644 AC XY: 4787 AN XY: 74384

African (AFR) AF: 0.0921 AC: 3823 AN: 41506

American (AMR) AF: 0.139 AC: 2128 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3470

East Asian (EAS) AF: 0.0164 AC: 85 AN: 5178

South Asian (SAS) AF: 0.146 AC: 703 AN: 4812

European-Finnish (FIN) AF: 0.0579 AC: 613 AN: 10596

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0223 AC: 1514 AN: 67992

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0370 Hom.: 553

Bravo AF: 0.0641

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0200 AC: 77

ESP6500AA AF: 0.0951 AC: 419

ESP6500EA AF: 0.0221 AC: 190

ExAC AF: 0.0653 AC: 7925

Asia WGS AF: 0.105 AC: 364 AN: 3478

EpiCase AF: 0.0215

EpiControl AF: 0.0219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.94
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.66	T
PhyloP100		4.2
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.57
Sift	Benign	0.033	D
Sift4G	Uncertain	0.025	D
Polyphen		0.99	D
Vest4		0.071
MPC		0.24
ClinPred		0.041	T
GERP RS		4.9
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: rs4894048; hg19: chr2-179638721;