chr2-178541317-C-T

Variant names:

• chr2-178541317-C-T
• rs55704830
• NM_001267550.2:c.97760G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.97760G>A​(p.Arg32587His) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,546,330 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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. R32587P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16
• Conservation: PhyloP100: 3.85
• Publications: 10 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]

ENSG00000270956 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072649717).
• BP6: Variant 2-178541317-C-T is Benign according to our data. Variant chr2-178541317-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00303 (461/152250) while in subpopulation AFR AF = 0.00448 (186/41536). AF 95% confidence interval is 0.00395. There are 1 homozygotes in GnomAd4. There are 203 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

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.97760G>A	p.Arg32587His	missense	Exon 350 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.92837G>A	p.Arg30946His	missense	Exon 300 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.90056G>A	p.Arg30019His	missense	Exon 299 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.97760G>A	p.Arg32587His	missense	Exon 350 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.97604G>A	p.Arg32535His	missense	Exon 348 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.97484G>A	p.Arg32495His	missense	Exon 348 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 460 AN: 152132 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00341

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00173 AC: 291 AN: 167792 AF XY: 0.00145

Gnomad AFR exome AF: 0.00324

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.000356

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000581

Gnomad NFE exome AF: 0.00289

Gnomad OTH exome AF: 0.00174

GnomAD4 exome AF: 0.00269 AC: 3751 AN: 1394080 Hom.: 4 Cov.: 31 AF XY: 0.00260 AC XY: 1788 AN XY: 686982

African (AFR) AF: 0.00462 AC: 149 AN: 32220

American (AMR) AF: 0.00213 AC: 77 AN: 36196

Ashkenazi Jewish (ASJ) AF: 0.000121 AC: 3 AN: 24750

East Asian (EAS) AF: 0.00 AC: 0 AN: 36546

South Asian (SAS) AF: 0.000243 AC: 19 AN: 78210

European-Finnish (FIN) AF: 0.000961 AC: 48 AN: 49970

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5636

European-Non Finnish (NFE) AF: 0.00310 AC: 3326 AN: 1072704

Other (OTH) AF: 0.00213 AC: 123 AN: 57848

GnomAD4 genome AF: 0.00303 AC: 461 AN: 152250 Hom.: 1 Cov.: 33 AF XY: 0.00273 AC XY: 203 AN XY: 74442

African (AFR) AF: 0.00448 AC: 186 AN: 41536

American (AMR) AF: 0.00203 AC: 31 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00341 AC: 232 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00266 Hom.: 5

Bravo AF: 0.00305

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00362 AC: 14

ESP6500EA AF: 0.00376 AC: 31

ExAC AF: 0.00158 AC: 186

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Cardiomyopathy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	22
DANN	Benign	0.97
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.0073	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.94	L
PhyloP100		3.8
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.21
Sift	Benign	0.059	T
Polyphen		1.0	D
Vest4		0.37
MVP		0.21
MPC		0.36
ClinPred		0.019	T
GERP RS		5.7
Mutation Taster		=79/21	polymorphism

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: rs55704830; hg19: chr2-179406044; COSMIC: COSV60286041; COSMIC: COSV60286041;