chr2-178779308-G-A

Variant names:

• chr2-178779308-G-A
• rs1552280
• NM_001267550.2:c.3884C>T

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.3884C>T​(p.Ser1295Leu) variant causes a missense change. The variant allele was found at a frequency of 0.978 in 1,613,600 control chromosomes in the GnomAD database, including 772,469 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.95 (68587 hom., cov: 32)
  • Exomes 𝑓: 0.98 (703882 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 6.29
• Publications: 38 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]

LOC101927055 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=6.196605E-7).
• BP6: Variant 2-178779308-G-A is Benign according to our data. Variant chr2-178779308-G-A is described in ClinVar as Benign. ClinVar VariationId is 47001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 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.3884C>T	p.Ser1295Leu	missense	Exon 23 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.3884C>T	p.Ser1295Leu	missense	Exon 23 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.3884C>T	p.Ser1295Leu	missense	Exon 23 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.3884C>T	p.Ser1295Leu	missense	Exon 23 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.3884C>T	p.Ser1295Leu	missense	Exon 23 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.3608C>T	p.Ser1203Leu	missense	Exon 21 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.948 AC: 144176 AN: 152132 Hom.: 68561 Cov.: 32

Gnomad AFR AF: 0.869

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.964

Gnomad ASJ AF: 0.994

Gnomad EAS AF: 0.872

Gnomad SAS AF: 0.951

Gnomad FIN AF: 0.980

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.948

GnomAD2 exomes AF: 0.962 AC: 240635 AN: 250190 AF XY: 0.965

Gnomad AFR exome AF: 0.869

Gnomad AMR exome AF: 0.939

Gnomad ASJ exome AF: 0.992

Gnomad EAS exome AF: 0.881

Gnomad FIN exome AF: 0.978

Gnomad NFE exome AF: 0.990

Gnomad OTH exome AF: 0.970

GnomAD4 exome AF: 0.981 AC: 1433607 AN: 1461350 Hom.: 703882 Cov.: 54 AF XY: 0.981 AC XY: 713137 AN XY: 726998

African (AFR) AF: 0.866 AC: 28958 AN: 33456

American (AMR) AF: 0.943 AC: 42162 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.993 AC: 25933 AN: 26122

East Asian (EAS) AF: 0.870 AC: 34463 AN: 39624

South Asian (SAS) AF: 0.958 AC: 82651 AN: 86234

European-Finnish (FIN) AF: 0.977 AC: 52171 AN: 53384

Middle Eastern (MID) AF: 0.985 AC: 5679 AN: 5766

European-Non Finnish (NFE) AF: 0.992 AC: 1102995 AN: 1111692

Other (OTH) AF: 0.971 AC: 58595 AN: 60364

GnomAD4 genome AF: 0.947 AC: 144254 AN: 152250 Hom.: 68587 Cov.: 32 AF XY: 0.948 AC XY: 70544 AN XY: 74432

African (AFR) AF: 0.868 AC: 36059 AN: 41522

American (AMR) AF: 0.964 AC: 14721 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 3449 AN: 3470

East Asian (EAS) AF: 0.872 AC: 4520 AN: 5182

South Asian (SAS) AF: 0.951 AC: 4590 AN: 4826

European-Finnish (FIN) AF: 0.980 AC: 10408 AN: 10618

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67446 AN: 68038

Other (OTH) AF: 0.948 AC: 2005 AN: 2114

Alfa AF: 0.975 Hom.: 246799

Bravo AF: 0.940

TwinsUK AF: 0.992 AC: 3680

ALSPAC AF: 0.992 AC: 3825

ESP6500AA AF: 0.872 AC: 3841

ESP6500EA AF: 0.991 AC: 8524

ExAC AF: 0.960 AC: 116549

Asia WGS AF: 0.907 AC: 3156 AN: 3478

EpiCase AF: 0.991

EpiControl AF: 0.991

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	13	not specified (13)
-	-	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	0.036
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.084	T
MetaRNN	Benign	6.2e-7	T
MetaSVM	Benign	-0.96	T
PhyloP100		6.3
PrimateAI	Benign	0.35	T
PROVEAN	Benign	2.2	N
REVEL	Benign	0.18
Sift	Benign	0.33	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.038
MPC		0.074
ClinPred		0.017	T
GERP RS		5.7
Mutation Taster		=87/13	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: rs1552280; hg19: chr2-179644035; COSMIC: COSV104640964; COSMIC: COSV104640964;