rs6723526

Variant names:

• chr2-178633315-T-C
• rs6723526
• NM_001267550.2:c.42958A>G

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.42958A>G​(p.Lys14320Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0976 in 1,612,778 control chromosomes in the GnomAD database, including 8,427 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (511 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7916 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 7.97
• Publications: 24 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=0.001886487).
• BP6: Variant 2-178633315-T-C is Benign according to our data. Variant chr2-178633315-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.105 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.42958A>G	p.Lys14320Glu	missense	Exon 233 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.38035A>G	p.Lys12679Glu	missense	Exon 183 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.35254A>G	p.Lys11752Glu	missense	Exon 182 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.42958A>G	p.Lys14320Glu	missense	Exon 233 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.42802A>G	p.Lys14268Glu	missense	Exon 231 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.42682A>G	p.Lys14228Glu	missense	Exon 231 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 10990 AN: 152028 Hom.: 511 Cov.: 32

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.0590

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.00621

Gnomad SAS AF: 0.0990

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.0774

GnomAD2 exomes AF: 0.0824 AC: 20425 AN: 247906 AF XY: 0.0877

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.0421

Gnomad ASJ exome AF: 0.0694

Gnomad EAS exome AF: 0.00620

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.107

Gnomad OTH exome AF: 0.0937

GnomAD4 exome AF: 0.100 AC: 146375 AN: 1460632 Hom.: 7916 Cov.: 34 AF XY: 0.101 AC XY: 73474 AN XY: 726510

African (AFR) AF: 0.0144 AC: 481 AN: 33386

American (AMR) AF: 0.0440 AC: 1963 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 1782 AN: 26108

East Asian (EAS) AF: 0.0106 AC: 422 AN: 39646

South Asian (SAS) AF: 0.106 AC: 9100 AN: 86002

European-Finnish (FIN) AF: 0.0996 AC: 5321 AN: 53398

Middle Eastern (MID) AF: 0.0947 AC: 545 AN: 5754

European-Non Finnish (NFE) AF: 0.109 AC: 121293 AN: 1111384

Other (OTH) AF: 0.0906 AC: 5468 AN: 60320

GnomAD4 genome AF: 0.0723 AC: 11000 AN: 152146 Hom.: 511 Cov.: 32 AF XY: 0.0724 AC XY: 5380 AN XY: 74360

African (AFR) AF: 0.0178 AC: 741 AN: 41546

American (AMR) AF: 0.0589 AC: 900 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 230 AN: 3470

East Asian (EAS) AF: 0.00622 AC: 32 AN: 5144

South Asian (SAS) AF: 0.101 AC: 487 AN: 4816

European-Finnish (FIN) AF: 0.103 AC: 1088 AN: 10610

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.107 AC: 7284 AN: 67962

Other (OTH) AF: 0.0766 AC: 162 AN: 2114

Alfa AF: 0.0933 Hom.: 3280

Bravo AF: 0.0654

TwinsUK AF: 0.109 AC: 404

ALSPAC AF: 0.105 AC: 404

ESP6500AA AF: 0.0180 AC: 66

ESP6500EA AF: 0.110 AC: 898

ExAC AF: 0.0829 AC: 10009

Asia WGS AF: 0.0520 AC: 179 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.104

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	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)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.94
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Benign	0.089	T
Polyphen		1.0	D
Vest4		0.30
MPC		0.54
ClinPred		0.018	T
GERP RS		6.2
Mutation Taster		=91/9	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs6723526; hg19: chr2-179498042; COSMIC: COSV59911372; COSMIC: COSV59911372;