rs727503577

Variant names:

• chr2-178580183-T-G
• rs727503577
• NM_001267550.2:c.67104A>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001267550.2(TTN):​c.67104A>C​(p.Lys22368Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: 0.454
• 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]

ENSG00000270574 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10390934).
• BP6: Variant 2-178580183-T-G is Benign according to our data. Variant chr2-178580183-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165883.

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.67104A>C	p.Lys22368Asn	missense	Exon 318 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.62181A>C	p.Lys20727Asn	missense	Exon 268 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.59400A>C	p.Lys19800Asn	missense	Exon 267 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.67104A>C	p.Lys22368Asn	missense	Exon 318 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.66948A>C	p.Lys22316Asn	missense	Exon 316 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.66828A>C	p.Lys22276Asn	missense	Exon 316 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00144

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: 0.00

GnomAD2 exomes AF: 0.0000444 AC: 11 AN: 247962 AF XY: 0.0000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000997

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000329 AC: 48 AN: 1460960 Hom.: 0 Cov.: 36 AF XY: 0.0000289 AC XY: 21 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 33 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111492

Other (OTH) AF: 0.0000663 AC: 4 AN: 60322

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152112 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74280

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000414 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	2	not specified (4)
-	1	1	not provided (2)
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	17
DANN	Benign	0.94
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.45
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.17
Sift	Uncertain	0.026	D
Polyphen		0.97	D
Vest4		0.28
MutPred		0.52		Loss of ubiquitination at K20727 (P = 0.0081)
MVP		0.21
MPC		0.21
ClinPred		0.20	T
GERP RS		4.5
Mutation Taster		=63/37	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: rs727503577; hg19: chr2-179444910;