rs75031300

Variant names:

• chr2-178774107-C-T
• rs75031300
• NM_001267550.2:c.7061G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.7061G>A​(p.Arg2354His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000538 in 1,613,940 control chromosomes in the GnomAD database, including 8 homozygotes. 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. R2354C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: 7.91
• Publications: 17 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008191109).
• BP6: Variant 2-178774107-C-T is Benign according to our data. Variant chr2-178774107-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47365.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0026 (396/152194) while in subpopulation AFR AF = 0.00898 (373/41518). AF 95% confidence interval is 0.00823. There are 4 homozygotes in GnomAd4. There are 176 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.7061G>A	p.Arg2354His	missense	Exon 31 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.7061G>A	p.Arg2354His	missense	Exon 31 of 313	NP_001243779.1
	TTN	NM_133378.4		c.7061G>A	p.Arg2354His	missense	Exon 31 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.7061G>A	p.Arg2354His	missense	Exon 31 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.7061G>A	p.Arg2354His	missense	Exon 31 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.6785G>A	p.Arg2262His	missense	Exon 29 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152076 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00899

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000739 AC: 185 AN: 250194 AF XY: 0.000553

Gnomad AFR exome AF: 0.00979

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000324 AC: 473 AN: 1461746 Hom.: 4 Cov.: 33 AF XY: 0.000296 AC XY: 215 AN XY: 727180

African (AFR) AF: 0.00998 AC: 334 AN: 33472

American (AMR) AF: 0.000626 AC: 28 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111958

Other (OTH) AF: 0.000778 AC: 47 AN: 60392

GnomAD4 genome AF: 0.00260 AC: 396 AN: 152194 Hom.: 4 Cov.: 32 AF XY: 0.00237 AC XY: 176 AN XY: 74416

African (AFR) AF: 0.00898 AC: 373 AN: 41518

American (AMR) AF: 0.000458 AC: 7 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68004

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.000969 Hom.: 3

Bravo AF: 0.00316

ESP6500AA AF: 0.00953 AC: 42

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000923 AC: 112

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	3	not provided (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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.69	T
PhyloP100		7.9
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.38
Sift	Benign	0.11	T
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.30
MVP		0.23
MPC		0.51
ClinPred		0.031	T
GERP RS		5.7
Mutation Taster		=97/3	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: rs75031300; hg19: chr2-179638834; COSMIC: COSV59910057; COSMIC: COSV59910057;