2-178567458-A-G

Variant names:

• chr2-178567458-A-G
• rs12463674
• NM_001267550.2:c.78674T>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.78674T>C​(p.Ile26225Thr) variant causes a missense change. The variant allele was found at a frequency of 0.279 in 1,612,278 control chromosomes in the GnomAD database, including 68,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4612 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63620 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 6.00
• Publications: 42 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=0.0015751421).
• BP6: Variant 2-178567458-A-G is Benign according to our data. Variant chr2-178567458-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 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.78674T>C	p.Ile26225Thr	missense	Exon 326 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.73751T>C	p.Ile24584Thr	missense	Exon 276 of 313	NP_001243779.1
	TTN	NM_133378.4		c.70970T>C	p.Ile23657Thr	missense	Exon 275 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.78674T>C	p.Ile26225Thr	missense	Exon 326 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.78518T>C	p.Ile26173Thr	missense	Exon 324 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.78398T>C	p.Ile26133Thr	missense	Exon 324 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.214 AC: 32506 AN: 151860 Hom.: 4615 Cov.: 32

Gnomad AFR AF: 0.0538

Gnomad AMI AF: 0.225

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.241

Gnomad NFE AF: 0.311

Gnomad OTH AF: 0.203

GnomAD2 exomes AF: 0.234 AC: 58037 AN: 247890 AF XY: 0.241

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.111

Gnomad ASJ exome AF: 0.210

Gnomad EAS exome AF: 0.0453

Gnomad FIN exome AF: 0.382

Gnomad NFE exome AF: 0.305

Gnomad OTH exome AF: 0.235

GnomAD4 exome AF: 0.286 AC: 417111 AN: 1460300 Hom.: 63620 Cov.: 49 AF XY: 0.284 AC XY: 206479 AN XY: 726366

African (AFR) AF: 0.0417 AC: 1394 AN: 33418

American (AMR) AF: 0.113 AC: 5042 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.212 AC: 5524 AN: 26078

East Asian (EAS) AF: 0.0497 AC: 1971 AN: 39650

South Asian (SAS) AF: 0.223 AC: 19181 AN: 86028

European-Finnish (FIN) AF: 0.378 AC: 20129 AN: 53310

Middle Eastern (MID) AF: 0.208 AC: 1199 AN: 5754

European-Non Finnish (NFE) AF: 0.312 AC: 347131 AN: 1111102

Other (OTH) AF: 0.258 AC: 15540 AN: 60320

GnomAD4 genome AF: 0.214 AC: 32495 AN: 151978 Hom.: 4612 Cov.: 32 AF XY: 0.213 AC XY: 15835 AN XY: 74256

African (AFR) AF: 0.0536 AC: 2226 AN: 41512

American (AMR) AF: 0.152 AC: 2324 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3468

East Asian (EAS) AF: 0.0520 AC: 268 AN: 5154

South Asian (SAS) AF: 0.225 AC: 1083 AN: 4820

European-Finnish (FIN) AF: 0.386 AC: 4072 AN: 10540

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.311 AC: 21093 AN: 67920

Other (OTH) AF: 0.201 AC: 424 AN: 2110

Alfa AF: 0.268 Hom.: 22533

Bravo AF: 0.185

TwinsUK AF: 0.311 AC: 1155

ALSPAC AF: 0.324 AC: 1248

ESP6500AA AF: 0.0543 AC: 200

ESP6500EA AF: 0.303 AC: 2480

ExAC AF: 0.236 AC: 28509

Asia WGS AF: 0.124 AC: 432 AN: 3478

EpiCase AF: 0.296

EpiControl AF: 0.284

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	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	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	20
DANN	Benign	0.92
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.0
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.44
Sift	Benign	0.056	T
Polyphen		0.68	P
Vest4		0.40
MPC		0.16
ClinPred		0.033	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs12463674; hg19: chr2-179432185; COSMIC: COSV59946130;