rs111727915

Variant names:

• chr2-178554626-C-T
• rs111727915
• NM_001267550.2:c.88721G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.88721G>A​(p.Arg29574His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000315 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R29574C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:9
• Conservation: PhyloP100: 7.91
• Publications: 11 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]

ENSG00000279598 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023333669).
• BP6: Variant 2-178554626-C-T is Benign according to our data. Variant chr2-178554626-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47483.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000873 (133/152282) while in subpopulation AFR AF = 0.00204 (85/41566). AF 95% confidence interval is 0.00169. There are 0 homozygotes in GnomAd4. There are 64 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.88721G>A	p.Arg29574His	missense	Exon 332 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.83798G>A	p.Arg27933His	missense	Exon 282 of 313	NP_001243779.1
	TTN	NM_133378.4		c.81017G>A	p.Arg27006His	missense	Exon 281 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.88721G>A	p.Arg29574His	missense	Exon 332 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.88565G>A	p.Arg29522His	missense	Exon 330 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.88445G>A	p.Arg29482His	missense	Exon 330 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000495 AC: 123 AN: 248686 AF XY: 0.000400

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.000985

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000338

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.000257 AC: 375 AN: 1461634 Hom.: 0 Cov.: 32 AF XY: 0.000232 AC XY: 169 AN XY: 727106

African (AFR) AF: 0.00191 AC: 64 AN: 33478

American (AMR) AF: 0.000872 AC: 39 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 41 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53398

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5766

European-Non Finnish (NFE) AF: 0.000162 AC: 180 AN: 1111822

Other (OTH) AF: 0.000596 AC: 36 AN: 60368

GnomAD4 genome AF: 0.000873 AC: 133 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000859 AC XY: 64 AN XY: 74470

African (AFR) AF: 0.00204 AC: 85 AN: 41566

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000708 Hom.: 0

Bravo AF: 0.00128

ESP6500AA AF: 0.00171 AC: 7

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000413 AC: 50

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	2	not specified (3)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (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)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.023	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.5	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.37
MPC		0.52
ClinPred		0.042	T
GERP RS		5.7
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: rs111727915; hg19: chr2-179419353; COSMIC: COSV60377897; COSMIC: COSV60377897;