2-178534812-T-C

Variant names:

• chr2-178534812-T-C
• rs56376197
• NM_001267550.2:c.101803A>G

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.101803A>G​(p.Ile33935Val) variant causes a missense change. The variant allele was found at a frequency of 0.00272 in 1,611,264 control chromosomes in the GnomAD database, including 129 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. I33935M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (64 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (65 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 4.00
• Publications: 9 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=0.0019720793).
• BP6: Variant 2-178534812-T-C is Benign according to our data. Variant chr2-178534812-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47642.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0503 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.101803A>G	p.Ile33935Val	missense	Exon 358 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.96880A>G	p.Ile32294Val	missense	Exon 308 of 313	NP_001243779.1
	TTN	NM_133378.4		c.94099A>G	p.Ile31367Val	missense	Exon 307 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.101803A>G	p.Ile33935Val	missense	Exon 358 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.101647A>G	p.Ile33883Val	missense	Exon 356 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.101527A>G	p.Ile33843Val	missense	Exon 356 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0149 AC: 2269 AN: 152202 Hom.: 64 Cov.: 33

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00366 AC: 902 AN: 246558 AF XY: 0.00287

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000711

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00145 AC: 2116 AN: 1458944 Hom.: 65 Cov.: 37 AF XY: 0.00117 AC XY: 852 AN XY: 725894

African (AFR) AF: 0.0534 AC: 1788 AN: 33464

American (AMR) AF: 0.00264 AC: 118 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50774

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5764

European-Non Finnish (NFE) AF: 0.0000360 AC: 40 AN: 1111786

Other (OTH) AF: 0.00262 AC: 158 AN: 60356

GnomAD4 genome AF: 0.0149 AC: 2274 AN: 152320 Hom.: 64 Cov.: 33 AF XY: 0.0148 AC XY: 1106 AN XY: 74488

African (AFR) AF: 0.0521 AC: 2167 AN: 41570

American (AMR) AF: 0.00510 AC: 78 AN: 15294

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

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

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000220 AC: 15 AN: 68034

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00460 Hom.: 38

Bravo AF: 0.0167

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0486 AC: 180

ESP6500EA AF: 0.000366 AC: 3

ExAC AF: 0.00435 AC: 525

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

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	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	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Benign	0.87
Eigen	Benign	0.045
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.0
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.085
Sift	Benign	0.049	D
Polyphen		0.076	B
Vest4		0.31
MVP		0.57
MPC		0.077
ClinPred		0.041	T
GERP RS		6.0
Mutation Taster		=99/1	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: rs56376197; hg19: chr2-179399539;