rs59887778

Variant names:

• chr2-178672228-C-T
• rs59887778
• NM_001267550.2:c.34970G>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.34970G>A​(p.Arg11657His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,566,538 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 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. R11657C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (16 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 1.99
• Publications: 5 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=0.0024925768).
• BP6: Variant 2-178672228-C-T is Benign according to our data. Variant chr2-178672228-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46911.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 = 0.00705 (1071/151840) while in subpopulation AFR AF = 0.0245 (1016/41498). AF 95% confidence interval is 0.0232. There are 12 homozygotes in GnomAd4. There are 493 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.34970G>A	p.Arg11657His	missense	Exon 155 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.33848G>A	p.Arg11283His	missense	Exon 151 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31067G>A	p.Arg10356His	missense	Exon 150 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.34970G>A	p.Arg11657His	missense	Exon 155 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.34970G>A	p.Arg11657His	missense	Exon 155 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34694G>A	p.Arg11565His	missense	Exon 153 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00701 AC: 1064 AN: 151722 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00217

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00175 AC: 313 AN: 179188 AF XY: 0.00124

Gnomad AFR exome AF: 0.0269

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000409

Gnomad OTH exome AF: 0.000409

GnomAD4 exome AF: 0.000679 AC: 960 AN: 1414698 Hom.: 16 Cov.: 31 AF XY: 0.000621 AC XY: 435 AN XY: 700136

African (AFR) AF: 0.0235 AC: 748 AN: 31826

American (AMR) AF: 0.00113 AC: 42 AN: 37280

Ashkenazi Jewish (ASJ) AF: 0.0000785 AC: 2 AN: 25462

East Asian (EAS) AF: 0.0000553 AC: 2 AN: 36156

South Asian (SAS) AF: 0.000158 AC: 13 AN: 82334

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50384

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5718

European-Non Finnish (NFE) AF: 0.0000294 AC: 32 AN: 1086920

Other (OTH) AF: 0.00194 AC: 114 AN: 58618

GnomAD4 genome AF: 0.00705 AC: 1071 AN: 151840 Hom.: 12 Cov.: 32 AF XY: 0.00664 AC XY: 493 AN XY: 74210

African (AFR) AF: 0.0245 AC: 1016 AN: 41498

American (AMR) AF: 0.00217 AC: 33 AN: 15194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 67784

Other (OTH) AF: 0.00617 AC: 13 AN: 2106

Alfa AF: 0.00241 Hom.: 10

Bravo AF: 0.00782

ESP6500AA AF: 0.0231 AC: 81

ESP6500EA AF: 0.000127 AC: 1

ExAC AF: 0.00173 AC: 197

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	3	not provided (3)
-	-	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	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	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	0.062
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.67
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.6	N
PhyloP100		2.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.052
Sift	Benign	0.066	T
Polyphen		0.0	B
Vest4		0.034
MVP		0.11
MPC		0.10
ClinPred		0.0071	T
GERP RS		3.0
PromoterAI		-0.031	Neutral
Mutation Taster		=97/3	polymorphism

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: rs59887778; hg19: chr2-179536955; COSMIC: COSV60016194; COSMIC: COSV60016194;