NM_001267550.2:c.16529A>G

Variant names:

• chr2-178732532-T-C
• rs72648939
• NM_001267550.2:c.16529A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.16529A>G​(p.Tyr5510Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000831 in 1,613,728 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y5510Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00079 (23 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:26
• Conservation: PhyloP100: 6.27
• Publications: 8 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=0.0060405433).
• BP6: Variant 2-178732532-T-C is Benign according to our data. Variant chr2-178732532-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0012 (182/152292) while in subpopulation EAS AF = 0.0278 (144/5176). AF 95% confidence interval is 0.0241. There are 6 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.16529A>G	p.Tyr5510Cys	missense	Exon 56 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.15578A>G	p.Tyr5193Cys	missense	Exon 54 of 313	NP_001243779.1
	TTN	NM_133378.4		c.12797A>G	p.Tyr4266Cys	missense	Exon 53 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.16529A>G	p.Tyr5510Cys	missense	Exon 56 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.16529A>G	p.Tyr5510Cys	missense	Exon 56 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.16253A>G	p.Tyr5418Cys	missense	Exon 54 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152174 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0279

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00227 AC: 564 AN: 248318 AF XY: 0.00206

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0290

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000890

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000793 AC: 1159 AN: 1461436 Hom.: 23 Cov.: 36 AF XY: 0.000766 AC XY: 557 AN XY: 727012

African (AFR) AF: 0.000359 AC: 12 AN: 33468

American (AMR) AF: 0.000291 AC: 13 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.0212 AC: 841 AN: 39652

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.0000342 AC: 38 AN: 1111748

Other (OTH) AF: 0.00376 AC: 227 AN: 60356

GnomAD4 genome AF: 0.00120 AC: 182 AN: 152292 Hom.: 6 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74448

African (AFR) AF: 0.000553 AC: 23 AN: 41586

American (AMR) AF: 0.000262 AC: 4 AN: 15290

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

East Asian (EAS) AF: 0.0278 AC: 144 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00122 Hom.: 13

Bravo AF: 0.00171

ESP6500AA AF: 0.000808 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00223 AC: 269

Asia WGS AF: 0.0200 AC: 68 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	5	not provided (5)
-	-	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	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Benign	0.80
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.36	T
PhyloP100		6.3
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.41
Sift	Benign	0.082	T
Polyphen		1.0	D
Vest4		0.50
MVP		0.69
MPC		0.47
ClinPred		0.030	T
GERP RS		6.2
Mutation Taster		=78/22	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: rs72648939; hg19: chr2-179597259;