rs397517599

Variant names:

• chr2-178611946-A-G
• rs397517599
• NM_001267550.2:c.50363T>C

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.50363T>C​(p.Ile16788Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000364 in 1,611,272 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: 9.27
• Publications: 3 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=0.009715587).
• BP6: Variant 2-178611946-A-G is Benign according to our data. Variant chr2-178611946-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47042.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000164 (25/152106) while in subpopulation SAS AF = 0.00497 (24/4830). AF 95% confidence interval is 0.00343. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 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.50363T>C	p.Ile16788Thr	missense	Exon 268 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.45440T>C	p.Ile15147Thr	missense	Exon 218 of 313	NP_001243779.1
	TTN	NM_133378.4		c.42659T>C	p.Ile14220Thr	missense	Exon 217 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.50363T>C	p.Ile16788Thr	missense	Exon 268 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.50207T>C	p.Ile16736Thr	missense	Exon 266 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.50087T>C	p.Ile16696Thr	missense	Exon 266 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 151988 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00496

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000886 AC: 218 AN: 246026 AF XY: 0.00115

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000588

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000538

Gnomad OTH exome AF: 0.000336

GnomAD4 exome AF: 0.000384 AC: 561 AN: 1459166 Hom.: 9 Cov.: 33 AF XY: 0.000579 AC XY: 420 AN XY: 725868

African (AFR) AF: 0.0000301 AC: 1 AN: 33238

American (AMR) AF: 0.0000677 AC: 3 AN: 44312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00607 AC: 521 AN: 85794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5744

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111032

Other (OTH) AF: 0.000498 AC: 30 AN: 60236

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152106 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5116

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000136 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000895 AC: 108

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Benign	0.87
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0097	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.53
MutPred		0.59		Gain of phosphorylation at I15147 (P = 0.0108)
MVP		0.75
MPC		0.42
ClinPred		0.17	T
GERP RS		6.1
Mutation Taster		=93/7	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: rs397517599; hg19: chr2-179476673; COSMIC: COSV60223756; COSMIC: COSV60223756;