2-178632291-G-A

Variant names:

• chr2-178632291-G-A
• rs12471771
• NM_001267550.2:c.43603C>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.43603C>T​(p.Arg14535Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00545 in 1,609,396 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts 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. R14535H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0098 (94 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (623 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 5.54
• Publications: 6 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=0.0019354224).
• BP6: Variant 2-178632291-G-A is Benign according to our data. Variant chr2-178632291-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0846 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.43603C>T	p.Arg14535Cys	missense	Exon 236 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.38680C>T	p.Arg12894Cys	missense	Exon 186 of 313	NP_001243779.1
	TTN	NM_133378.4		c.35899C>T	p.Arg11967Cys	missense	Exon 185 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.43603C>T	p.Arg14535Cys	missense	Exon 236 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.43447C>T	p.Arg14483Cys	missense	Exon 234 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.43327C>T	p.Arg14443Cys	missense	Exon 234 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00977 AC: 1484 AN: 151968 Hom.: 93 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0882

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0236 AC: 5721 AN: 241922 AF XY: 0.0175

Gnomad AFR exome AF: 0.00264

Gnomad AMR exome AF: 0.166

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000577

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000639

Gnomad OTH exome AF: 0.0183

GnomAD4 exome AF: 0.00500 AC: 7282 AN: 1457310 Hom.: 623 Cov.: 32 AF XY: 0.00420 AC XY: 3042 AN XY: 724596

African (AFR) AF: 0.00177 AC: 59 AN: 33410

American (AMR) AF: 0.157 AC: 6900 AN: 44032

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25972

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39342

South Asian (SAS) AF: 0.0000585 AC: 5 AN: 85514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000396 AC: 44 AN: 1109896

Other (OTH) AF: 0.00452 AC: 272 AN: 60214

GnomAD4 genome AF: 0.00981 AC: 1492 AN: 152086 Hom.: 94 Cov.: 32 AF XY: 0.0106 AC XY: 790 AN XY: 74330

African (AFR) AF: 0.00234 AC: 97 AN: 41510

American (AMR) AF: 0.0886 AC: 1350 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000280 AC: 19 AN: 67976

Other (OTH) AF: 0.0119 AC: 25 AN: 2104

Alfa AF: 0.00363 Hom.: 97

Bravo AF: 0.0186

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00206 AC: 8

ESP6500EA AF: 0.000722 AC: 6

ExAC AF: 0.0171 AC: 2061

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Benign	0.96
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.38
MPC		0.54
ClinPred		0.058	T
GERP RS		6.0
Mutation Taster		=83/17	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: rs12471771; hg19: chr2-179497018;