rs10497520

Variant names:

• chr2-178780128-T-C
• rs10497520
• NM_001267550.2:c.3601A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-178780128-T-C
• chr2-178780128-T-A

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.3601A>G​(p.Lys1201Glu) variant causes a missense change. The variant allele was found at a frequency of 0.796 in 1,613,524 control chromosomes in the GnomAD database, including 533,853 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.69 (39520 hom., cov: 32)
  • Exomes 𝑓: 0.81 (494333 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 4.10
• Publications: 68 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=8.3291127E-7).
• BP6: Variant 2-178780128-T-C is Benign according to our data. Variant chr2-178780128-T-C is described in ClinVar as Benign. ClinVar VariationId is 46973.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.863 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.3601A>G	p.Lys1201Glu	missense	Exon 22 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.3601A>G	p.Lys1201Glu	missense	Exon 22 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.3601A>G	p.Lys1201Glu	missense	Exon 22 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.3601A>G	p.Lys1201Glu	missense	Exon 22 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.3601A>G	p.Lys1201Glu	missense	Exon 22 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.3325A>G	p.Lys1109Glu	missense	Exon 20 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.693 AC: 105237 AN: 151918 Hom.: 39528 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.668

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.855

Gnomad EAS AF: 0.215

Gnomad SAS AF: 0.571

Gnomad FIN AF: 0.818

Gnomad MID AF: 0.905

Gnomad NFE AF: 0.869

Gnomad OTH AF: 0.744

GnomAD2 exomes AF: 0.686 AC: 172226 AN: 250880 AF XY: 0.704

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.404

Gnomad ASJ exome AF: 0.847

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.821

Gnomad NFE exome AF: 0.869

Gnomad OTH exome AF: 0.758

GnomAD4 exome AF: 0.807 AC: 1179324 AN: 1461488 Hom.: 494333 Cov.: 50 AF XY: 0.804 AC XY: 584631 AN XY: 727082

African (AFR) AF: 0.450 AC: 15038 AN: 33452

American (AMR) AF: 0.423 AC: 18925 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.850 AC: 22208 AN: 26126

East Asian (EAS) AF: 0.207 AC: 8197 AN: 39624

South Asian (SAS) AF: 0.590 AC: 50895 AN: 86246

European-Finnish (FIN) AF: 0.820 AC: 43798 AN: 53414

Middle Eastern (MID) AF: 0.853 AC: 4919 AN: 5766

European-Non Finnish (NFE) AF: 0.871 AC: 968851 AN: 1111776

Other (OTH) AF: 0.770 AC: 46493 AN: 60370

GnomAD4 genome AF: 0.692 AC: 105236 AN: 152036 Hom.: 39520 Cov.: 32 AF XY: 0.683 AC XY: 50759 AN XY: 74308

African (AFR) AF: 0.467 AC: 19343 AN: 41422

American (AMR) AF: 0.581 AC: 8866 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.855 AC: 2970 AN: 3472

East Asian (EAS) AF: 0.215 AC: 1114 AN: 5174

South Asian (SAS) AF: 0.571 AC: 2751 AN: 4816

European-Finnish (FIN) AF: 0.818 AC: 8658 AN: 10578

Middle Eastern (MID) AF: 0.898 AC: 264 AN: 294

European-Non Finnish (NFE) AF: 0.869 AC: 59095 AN: 67986

Other (OTH) AF: 0.741 AC: 1566 AN: 2112

Alfa AF: 0.802 Hom.: 232029

Bravo AF: 0.657

TwinsUK AF: 0.877 AC: 3253

ALSPAC AF: 0.870 AC: 3354

ESP6500AA AF: 0.471 AC: 2074

ESP6500EA AF: 0.870 AC: 7484

ExAC AF: 0.694 AC: 84231

Asia WGS AF: 0.389 AC: 1353 AN: 3478

EpiCase AF: 0.876

EpiControl AF: 0.872

ClinVar

ClinVar submissions

Significance: 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	0.16
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Benign	0.97
Eigen	Benign	0.034
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	8.3e-7	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.20
Sift	Benign	0.43	T
Sift4G	Uncertain	0.043	D
Polyphen		0.044	B
Vest4		0.14
MPC		0.13
ClinPred		0.013	T
GERP RS		4.6
Mutation Taster		=97/3	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: rs10497520; hg19: chr2-179644855; COSMIC: COSV59895018; COSMIC: COSV59895018;