2-178531435-C-G

Variant names:

• chr2-178531435-C-G
• rs56308529
• NM_001267550.2:c.105180G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.105180G>C​(p.Glu35060Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0426 in 1,613,932 control chromosomes in the GnomAD database, including 1,667 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.034 (127 hom., cov: 32)
  • Exomes 𝑓: 0.043 (1540 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 0.0310
• Publications: 16 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014609098).
• BP6: Variant 2-178531435-C-G is Benign according to our data. Variant chr2-178531435-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47684.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0542 is higher than 0.05.

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.105180G>C	p.Glu35060Asp	missense	Exon 358 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.100257G>C	p.Glu33419Asp	missense	Exon 308 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.97476G>C	p.Glu32492Asp	missense	Exon 307 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.105180G>C	p.Glu35060Asp	missense	Exon 358 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.105024G>C	p.Glu35008Asp	missense	Exon 356 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.104904G>C	p.Glu34968Asp	missense	Exon 356 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5190 AN: 152188 Hom.: 127 Cov.: 32

Gnomad AFR AF: 0.00943

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.0576

Gnomad ASJ AF: 0.0357

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0283

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0467

Gnomad OTH AF: 0.0272

GnomAD2 exomes AF: 0.0408 AC: 10160 AN: 249004 AF XY: 0.0394

Gnomad AFR exome AF: 0.00704

Gnomad AMR exome AF: 0.0908

Gnomad ASJ exome AF: 0.0408

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.0246

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0407

GnomAD4 exome AF: 0.0435 AC: 63524 AN: 1461626 Hom.: 1540 Cov.: 41 AF XY: 0.0428 AC XY: 31132 AN XY: 727102

African (AFR) AF: 0.00717 AC: 240 AN: 33478

American (AMR) AF: 0.0870 AC: 3891 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 1000 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0270 AC: 2325 AN: 86258

European-Finnish (FIN) AF: 0.0249 AC: 1326 AN: 53338

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5768

European-Non Finnish (NFE) AF: 0.0469 AC: 52193 AN: 1111852

Other (OTH) AF: 0.0403 AC: 2432 AN: 60374

GnomAD4 genome AF: 0.0341 AC: 5188 AN: 152306 Hom.: 127 Cov.: 32 AF XY: 0.0333 AC XY: 2482 AN XY: 74452

African (AFR) AF: 0.00941 AC: 391 AN: 41570

American (AMR) AF: 0.0573 AC: 877 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0357 AC: 124 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0263 AC: 127 AN: 4824

European-Finnish (FIN) AF: 0.0283 AC: 300 AN: 10612

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0467 AC: 3177 AN: 68024

Other (OTH) AF: 0.0270 AC: 57 AN: 2114

Alfa AF: 0.0390 Hom.: 120

Bravo AF: 0.0375

TwinsUK AF: 0.0445 AC: 165

ALSPAC AF: 0.0501 AC: 193

ESP6500AA AF: 0.0113 AC: 43

ESP6500EA AF: 0.0436 AC: 360

ExAC AF: 0.0378 AC: 4565

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	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	0.23
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.2
DANN	Benign	0.73
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L
PhyloP100		0.031
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.035
Sift	Benign	0.21	T
Polyphen		0.026	B
Vest4		0.24
MutPred		0.14		Loss of MoRF binding (P = 0.134)
MPC		0.079
ClinPred		0.0031	T
GERP RS		3.7
Mutation Taster		=90/10	polymorphism (auto)

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: rs56308529; hg19: chr2-179396162;