rs145204073

Variant names:

• chr2-178729077-T-C
• rs145204073
• NM_001267550.2:c.18961A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.18961A>G​(p.Ile6321Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000259 in 1,612,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: 1.57
• Publications: 4 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065808).
• BP6: Variant 2-178729077-T-C is Benign according to our data. Variant chr2-178729077-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 137839.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00143 (217/152162) while in subpopulation AFR AF = 0.00505 (210/41548). AF 95% confidence interval is 0.00449. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.18961A>G	p.Ile6321Val	missense	Exon 65 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.18010A>G	p.Ile6004Val	missense	Exon 63 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.15229A>G	p.Ile5077Val	missense	Exon 62 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.18961A>G	p.Ile6321Val	missense	Exon 65 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.18961A>G	p.Ile6321Val	missense	Exon 65 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.18685A>G	p.Ile6229Val	missense	Exon 63 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152044 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00505

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000375 AC: 92 AN: 245198 AF XY: 0.000323

Gnomad AFR exome AF: 0.00551

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000905

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000138 AC: 201 AN: 1460298 Hom.: 0 Cov.: 32 AF XY: 0.000106 AC XY: 77 AN XY: 726358

African (AFR) AF: 0.00497 AC: 166 AN: 33434

American (AMR) AF: 0.000202 AC: 9 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111278

Other (OTH) AF: 0.000249 AC: 15 AN: 60306

GnomAD4 genome AF: 0.00143 AC: 217 AN: 152162 Hom.: 1 Cov.: 33 AF XY: 0.00132 AC XY: 98 AN XY: 74386

African (AFR) AF: 0.00505 AC: 210 AN: 41548

American (AMR) AF: 0.000327 AC: 5 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67970

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000508 Hom.: 2

Bravo AF: 0.00154

ESP6500AA AF: 0.00629 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000480 AC: 58

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	2	-	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Cardiomyopathy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (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	Benign	0.088
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	18
DANN	Benign	0.91
Eigen	Benign	-0.049
Eigen_PC	Benign	0.067
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.66	T
PhyloP100		1.6
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.39	N
REVEL	Benign	0.13
Sift	Benign	1.0	T
Polyphen		0.041	B
Vest4		0.30
MVP		0.39
MPC		0.081
ClinPred		0.020	T
GERP RS		4.8
Mutation Taster		=98/2	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: rs145204073; hg19: chr2-179593804; COSMIC: COSV60380173; COSMIC: COSV60380173;