rs13398235

Variant names:

• chr2-178713977-G-A
• rs13398235
• NM_001267550.2:c.26681C>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.26681C>T​(p.Pro8894Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0473 in 1,613,384 control chromosomes in the GnomAD database, including 3,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P8894P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.080 (791 hom., cov: 32)
  • Exomes 𝑓: 0.044 (3144 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21
• Conservation: PhyloP100: 3.70
• Publications: 11 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018868148).
• BP6: Variant 2-178713977-G-A is Benign according to our data. Variant chr2-178713977-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.153 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.26681C>T	p.Pro8894Leu	missense	Exon 92 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.25730C>T	p.Pro8577Leu	missense	Exon 90 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.22949C>T	p.Pro7650Leu	missense	Exon 89 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.26681C>T	p.Pro8894Leu	missense	Exon 92 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.26681C>T	p.Pro8894Leu	missense	Exon 92 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.26405C>T	p.Pro8802Leu	missense	Exon 90 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0795 AC: 12078 AN: 152008 Hom.: 768 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.0358

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0585

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0252

Gnomad OTH AF: 0.0690

GnomAD2 exomes AF: 0.0784 AC: 19500 AN: 248598 AF XY: 0.0758

Gnomad AFR exome AF: 0.152

Gnomad AMR exome AF: 0.190

Gnomad ASJ exome AF: 0.0409

Gnomad EAS exome AF: 0.0285

Gnomad FIN exome AF: 0.0576

Gnomad NFE exome AF: 0.0264

Gnomad OTH exome AF: 0.0598

GnomAD4 exome AF: 0.0439 AC: 64094 AN: 1461258 Hom.: 3144 Cov.: 31 AF XY: 0.0460 AC XY: 33433 AN XY: 726888

African (AFR) AF: 0.159 AC: 5332 AN: 33460

American (AMR) AF: 0.188 AC: 8389 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 1045 AN: 26130

East Asian (EAS) AF: 0.0136 AC: 538 AN: 39670

South Asian (SAS) AF: 0.159 AC: 13736 AN: 86224

European-Finnish (FIN) AF: 0.0590 AC: 3148 AN: 53376

Middle Eastern (MID) AF: 0.0418 AC: 241 AN: 5766

European-Non Finnish (NFE) AF: 0.0257 AC: 28522 AN: 1111632

Other (OTH) AF: 0.0521 AC: 3143 AN: 60340

GnomAD4 genome AF: 0.0798 AC: 12143 AN: 152126 Hom.: 791 Cov.: 32 AF XY: 0.0840 AC XY: 6250 AN XY: 74370

African (AFR) AF: 0.153 AC: 6350 AN: 41490

American (AMR) AF: 0.146 AC: 2226 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0358 AC: 124 AN: 3468

East Asian (EAS) AF: 0.0265 AC: 137 AN: 5172

South Asian (SAS) AF: 0.162 AC: 780 AN: 4812

European-Finnish (FIN) AF: 0.0585 AC: 619 AN: 10590

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0252 AC: 1711 AN: 68000

Other (OTH) AF: 0.0682 AC: 144 AN: 2110

Alfa AF: 0.0407 Hom.: 1138

Bravo AF: 0.0864

TwinsUK AF: 0.0240 AC: 89

ALSPAC AF: 0.0241 AC: 93

ESP6500AA AF: 0.140 AC: 531

ESP6500EA AF: 0.0256 AC: 211

ExAC AF: 0.0747 AC: 9025

Asia WGS AF: 0.118 AC: 409 AN: 3476

EpiCase AF: 0.0241

EpiControl AF: 0.0253

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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	21
DANN	Benign	0.81
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.092
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.7
PrimateAI	Benign	0.41	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.16
Sift	Benign	0.76	T
Polyphen		0.066	B
Vest4		0.10
MPC		0.088
ClinPred		0.023	T
GERP RS		6.1
Mutation Taster		=96/4	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: rs13398235; hg19: chr2-179578704; COSMIC: COSV60092646; COSMIC: COSV60092646;