rs36051007

Variant names:

• chr2-178681132-C-T
• rs36051007
• NM_001267550.2:c.33287G>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.33287G>A​(p.Arg11096His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.279 in 1,602,616 control chromosomes in the GnomAD database, including 68,020 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R11096C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.21 (4618 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63402 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: -2.08
• 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017898977).
• BP6: Variant 2-178681132-C-T is Benign according to our data. Variant chr2-178681132-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.308 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.33287G>A	p.Arg11096His	missense	Exon 138 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.32336G>A	p.Arg10779His	missense	Exon 136 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.29555G>A	p.Arg9852His	missense	Exon 135 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.33287G>A	p.Arg11096His	missense	Exon 138 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.33287G>A	p.Arg11096His	missense	Exon 138 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.33011G>A	p.Arg11004His	missense	Exon 136 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32417 AN: 151770 Hom.: 4621 Cov.: 32

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.205

Gnomad EAS AF: 0.0450

Gnomad SAS AF: 0.214

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.312

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.231 AC: 55369 AN: 239322 AF XY: 0.238

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.0377

Gnomad FIN exome AF: 0.380

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.286 AC: 414269 AN: 1450728 Hom.: 63402 Cov.: 33 AF XY: 0.284 AC XY: 204732 AN XY: 721132

African (AFR) AF: 0.0421 AC: 1379 AN: 32794

American (AMR) AF: 0.111 AC: 4740 AN: 42562

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 5300 AN: 25902

East Asian (EAS) AF: 0.0423 AC: 1673 AN: 39572

South Asian (SAS) AF: 0.213 AC: 17678 AN: 82980

European-Finnish (FIN) AF: 0.375 AC: 19951 AN: 53164

Middle Eastern (MID) AF: 0.203 AC: 1166 AN: 5738

European-Non Finnish (NFE) AF: 0.313 AC: 347000 AN: 1108068

Other (OTH) AF: 0.257 AC: 15382 AN: 59948

GnomAD4 genome AF: 0.213 AC: 32404 AN: 151888 Hom.: 4618 Cov.: 32 AF XY: 0.212 AC XY: 15768 AN XY: 74254

African (AFR) AF: 0.0537 AC: 2227 AN: 41498

American (AMR) AF: 0.152 AC: 2319 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 709 AN: 3462

East Asian (EAS) AF: 0.0449 AC: 233 AN: 5186

South Asian (SAS) AF: 0.214 AC: 1032 AN: 4824

European-Finnish (FIN) AF: 0.384 AC: 4054 AN: 10554

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.312 AC: 21131 AN: 67832

Other (OTH) AF: 0.199 AC: 419 AN: 2108

Alfa AF: 0.275 Hom.: 22371

Bravo AF: 0.184

TwinsUK AF: 0.311 AC: 1155

ALSPAC AF: 0.326 AC: 1257

ESP6500AA AF: 0.0528 AC: 190

ESP6500EA AF: 0.303 AC: 2467

ExAC AF: 0.233 AC: 28183

Asia WGS AF: 0.120 AC: 417 AN: 3478

EpiCase AF: 0.295

EpiControl AF: 0.283

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	0.056
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	5.8
DANN	Benign	0.85
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
PhyloP100		-2.1
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.29	N
REVEL	Benign	0.062
Sift	Benign	0.42	T
Polyphen		0.0	B
Vest4		0.034
MPC		0.10
ClinPred		0.0044	T
GERP RS		-2.8
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs36051007; hg19: chr2-179545859; COSMIC: COSV60215351;