NM_001267550.2:c.3668C>T

Variant names:

• chr2-178780061-G-A
• rs78269740
• NM_001267550.2:c.3668C>T

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.3668C>T​(p.Ala1223Val) variant causes a missense change. The variant allele was found at a frequency of 0.000757 in 1,613,558 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00041 (9 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 3.86
• Publications: 5 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]

LOC101927055 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0060610473).
• BP6: Variant 2-178780061-G-A is Benign according to our data. Variant chr2-178780061-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46978.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00409 (622/152146) while in subpopulation AFR AF = 0.0142 (590/41500). AF 95% confidence interval is 0.0133. There are 3 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.3668C>T	p.Ala1223Val	missense	Exon 22 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.3668C>T	p.Ala1223Val	missense	Exon 22 of 313	NP_001243779.1
	TTN	NM_133378.4		c.3668C>T	p.Ala1223Val	missense	Exon 22 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.3668C>T	p.Ala1223Val	missense	Exon 22 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.3668C>T	p.Ala1223Val	missense	Exon 22 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.3392C>T	p.Ala1131Val	missense	Exon 20 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00406 AC: 617 AN: 152028 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.0141

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.000956 AC: 240 AN: 250988 AF XY: 0.000744

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.000411 AC: 600 AN: 1461412 Hom.: 9 Cov.: 30 AF XY: 0.000342 AC XY: 249 AN XY: 727022

African (AFR) AF: 0.0145 AC: 486 AN: 33450

American (AMR) AF: 0.000783 AC: 35 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000353 AC: 2 AN: 5662

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111832

Other (OTH) AF: 0.00103 AC: 62 AN: 60360

GnomAD4 genome AF: 0.00409 AC: 622 AN: 152146 Hom.: 3 Cov.: 33 AF XY: 0.00421 AC XY: 313 AN XY: 74368

African (AFR) AF: 0.0142 AC: 590 AN: 41500

American (AMR) AF: 0.00137 AC: 21 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00125 Hom.: 3

Bravo AF: 0.00464

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0132 AC: 58

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00121 AC: 147

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-0.41	T
PhyloP100		3.9
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.29
Sift	Benign	0.030	D
Sift4G	Benign	0.066	T
Polyphen		1.0	D
Vest4		0.19
MVP		0.47
MPC		0.33
ClinPred		0.031	T
GERP RS		5.9
Mutation Taster		=96/4	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: rs78269740; hg19: chr2-179644788; COSMIC: COSV59981550; COSMIC: COSV59981550;