NM_001267550.2:c.76720T>C

Variant names:

• chr2-178569412-A-G
• rs3813245
• NM_001267550.2:c.76720T>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.76720T>C​(p.Tyr25574His) variant causes a missense change. The variant allele was found at a frequency of 0.0229 in 1,613,320 control chromosomes in the GnomAD database, including 526 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict 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. Y25574Y) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.020 (51 hom., cov: 33)
  • Exomes 𝑓: 0.023 (475 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 6.03
• 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=0.004454404).
• BP6: Variant 2-178569412-A-G is Benign according to our data. Variant chr2-178569412-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0557 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.76720T>C	p.Tyr25574His	missense	Exon 326 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.71797T>C	p.Tyr23933His	missense	Exon 276 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.69016T>C	p.Tyr23006His	missense	Exon 275 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.76720T>C	p.Tyr25574His	missense	Exon 326 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.76564T>C	p.Tyr25522His	missense	Exon 324 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.76444T>C	p.Tyr25482His	missense	Exon 324 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 3076 AN: 152062 Hom.: 51 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.0307

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.0611

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.0444

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0260 AC: 6457 AN: 247950 AF XY: 0.0246

Gnomad AFR exome AF: 0.00498

Gnomad AMR exome AF: 0.0338

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.0619

Gnomad FIN exome AF: 0.0472

Gnomad NFE exome AF: 0.0233

Gnomad OTH exome AF: 0.0258

GnomAD4 exome AF: 0.0232 AC: 33884 AN: 1461140 Hom.: 475 Cov.: 41 AF XY: 0.0228 AC XY: 16578 AN XY: 726846

African (AFR) AF: 0.00407 AC: 136 AN: 33444

American (AMR) AF: 0.0320 AC: 1428 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 375 AN: 26110

East Asian (EAS) AF: 0.0635 AC: 2515 AN: 39616

South Asian (SAS) AF: 0.00682 AC: 588 AN: 86194

European-Finnish (FIN) AF: 0.0483 AC: 2579 AN: 53388

Middle Eastern (MID) AF: 0.00990 AC: 57 AN: 5758

European-Non Finnish (NFE) AF: 0.0224 AC: 24891 AN: 1111590

Other (OTH) AF: 0.0218 AC: 1315 AN: 60346

GnomAD4 genome AF: 0.0202 AC: 3073 AN: 152180 Hom.: 51 Cov.: 33 AF XY: 0.0206 AC XY: 1535 AN XY: 74390

African (AFR) AF: 0.00450 AC: 187 AN: 41558

American (AMR) AF: 0.0218 AC: 333 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0190 AC: 66 AN: 3470

East Asian (EAS) AF: 0.0613 AC: 316 AN: 5156

South Asian (SAS) AF: 0.00766 AC: 37 AN: 4832

European-Finnish (FIN) AF: 0.0444 AC: 471 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1592 AN: 67974

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0225 Hom.: 200

Bravo AF: 0.0186

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0244 AC: 94

ESP6500AA AF: 0.00525 AC: 20

ESP6500EA AF: 0.0207 AC: 170

ExAC AF: 0.0262 AC: 3160

Asia WGS AF: 0.0280 AC: 96 AN: 3478

EpiCase AF: 0.0203

EpiControl AF: 0.0219

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	not provided (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	0.15
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.84
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.99	L
PhyloP100		6.0
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.19
Sift	Benign	0.40	T
Polyphen		0.94	P
Vest4		0.24
MPC		0.41
ClinPred		0.030	T
GERP RS		4.5
Mutation Taster		=99/1	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: rs3813245; hg19: chr2-179434139; COSMIC: COSV60085260;