chr2-178608347-G-C

Variant names:

• chr2-178608347-G-C
• rs199615557
• NM_001267550.2:c.52536C>G

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.52536C>G​(p.Asn17512Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,612,176 control chromosomes in the GnomAD database, including 1 homozygotes. 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). Synonymous variant affecting the same amino acid position (i.e. N17512N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:13
• Conservation: PhyloP100: 0.0720
• Publications: 6 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.070400685).
• BP6: Variant 2-178608347-G-C is Benign according to our data. Variant chr2-178608347-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 96294.

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.52536C>G	p.Asn17512Lys	missense	Exon 275 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.47613C>G	p.Asn15871Lys	missense	Exon 225 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.44832C>G	p.Asn14944Lys	missense	Exon 224 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.52536C>G	p.Asn17512Lys	missense	Exon 275 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.52380C>G	p.Asn17460Lys	missense	Exon 273 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.52260C>G	p.Asn17420Lys	missense	Exon 273 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 151904 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000332 AC: 82 AN: 246666 AF XY: 0.000306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000735

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000539 AC: 787 AN: 1460154 Hom.: 1 Cov.: 32 AF XY: 0.000544 AC XY: 395 AN XY: 726306

African (AFR) AF: 0.0000299 AC: 1 AN: 33418

American (AMR) AF: 0.0000224 AC: 1 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39432

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000693 AC: 770 AN: 1111184

Other (OTH) AF: 0.000182 AC: 11 AN: 60274

GnomAD4 genome AF: 0.000349 AC: 53 AN: 152022 Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17 AN XY: 74312

African (AFR) AF: 0.000193 AC: 8 AN: 41512

American (AMR) AF: 0.000131 AC: 2 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67922

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000523 Hom.: 0

Bravo AF: 0.000332

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000486 AC: 4

ExAC AF: 0.000282 AC: 34

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000437

EpiControl AF: 0.000773

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	7	not provided (10)
-	-	2	not specified (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	Cardiovascular phenotype (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	0.68
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	4.7
DANN	Benign	0.96
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.070	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.072
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.10
Sift	Uncertain	0.015	D
Polyphen		0.026	B
Vest4		0.41
MutPred		0.69		Gain of methylation at N15871 (P = 0.0264)
MVP		0.067
MPC		0.11
ClinPred		0.082	T
GERP RS		-3.0
Mutation Taster		=34/66	disease causing

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: rs199615557; hg19: chr2-179473074;