rs116676813

Variant names:

• chr2-178684404-C-T
• rs116676813
• NM_001267550.2:c.32648G>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.32648G>A​(p.Arg10883Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0157 in 1,613,186 control chromosomes in the GnomAD database, including 243 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (11 hom., cov: 32)
  • Exomes 𝑓: 0.016 (232 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.259
• Publications: 7 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=0.002788514).
• BP6: Variant 2-178684404-C-T is Benign according to our data. Variant chr2-178684404-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.012 (1819/152086) while in subpopulation NFE AF = 0.0177 (1203/67950). AF 95% confidence interval is 0.0169. There are 11 homozygotes in GnomAd4. There are 908 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.32648G>A	p.Arg10883Lys	missense	Exon 132 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31697G>A	p.Arg10566Lys	missense	Exon 130 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.28916G>A	p.Arg9639Lys	missense	Exon 129 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.32648G>A	p.Arg10883Lys	missense	Exon 132 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32648G>A	p.Arg10883Lys	missense	Exon 132 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32372G>A	p.Arg10791Lys	missense	Exon 130 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1819 AN: 151968 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00329

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00603

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0321

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.00907

GnomAD2 exomes AF: 0.0116 AC: 2878 AN: 248570 AF XY: 0.0112

Gnomad AFR exome AF: 0.00285

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000558

Gnomad FIN exome AF: 0.0295

Gnomad NFE exome AF: 0.0168

Gnomad OTH exome AF: 0.0101

GnomAD4 exome AF: 0.0161 AC: 23534 AN: 1461100 Hom.: 232 Cov.: 31 AF XY: 0.0158 AC XY: 11448 AN XY: 726812

African (AFR) AF: 0.00242 AC: 81 AN: 33460

American (AMR) AF: 0.00340 AC: 152 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00346 AC: 298 AN: 86158

European-Finnish (FIN) AF: 0.0288 AC: 1537 AN: 53378

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0185 AC: 20564 AN: 1111502

Other (OTH) AF: 0.0139 AC: 836 AN: 60344

GnomAD4 genome AF: 0.0120 AC: 1819 AN: 152086 Hom.: 11 Cov.: 32 AF XY: 0.0122 AC XY: 908 AN XY: 74336

African (AFR) AF: 0.00328 AC: 136 AN: 41484

American (AMR) AF: 0.00602 AC: 92 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3466

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4816

European-Finnish (FIN) AF: 0.0321 AC: 340 AN: 10586

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

European-Non Finnish (NFE) AF: 0.0177 AC: 1203 AN: 67950

Other (OTH) AF: 0.00898 AC: 19 AN: 2116

Alfa AF: 0.0143 Hom.: 55

Bravo AF: 0.00931

TwinsUK AF: 0.0227 AC: 84

ALSPAC AF: 0.0189 AC: 73

ESP6500AA AF: 0.00274 AC: 10

ESP6500EA AF: 0.0180 AC: 147

ExAC AF: 0.0120 AC: 1453

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0142

EpiControl AF: 0.0150

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.92
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.26
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.096
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.068
MPC		0.084
ClinPred		0.011	T
GERP RS		1.4
Mutation Taster		=94/6	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: rs116676813; hg19: chr2-179549131;