NM_001267550.2:c.20175A>G

Variant names:

• chr2-178727190-T-C
• rs146627500
• NM_001267550.2:c.20175A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.20175A>G​(p.Ile6725Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00217 in 1,613,298 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 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 0.0018 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (47 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21
• Conservation: PhyloP100: -0.713
• Publications: 9 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]

ENSG00000267784 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003027141).
• BP6: Variant 2-178727190-T-C is Benign according to our data. Variant chr2-178727190-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46667.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00177 (269/152226) while in subpopulation SAS AF = 0.0244 (118/4828). AF 95% confidence interval is 0.0209. There are 5 homozygotes in GnomAd4. There are 153 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR gene

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.20175A>G	p.Ile6725Met	missense	Exon 69 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.19224A>G	p.Ile6408Met	missense	Exon 67 of 313	NP_001243779.1
	TTN	NM_133378.4		c.16443A>G	p.Ile5481Met	missense	Exon 66 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.20175A>G	p.Ile6725Met	missense	Exon 69 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.20175A>G	p.Ile6725Met	missense	Exon 69 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.19899A>G	p.Ile6633Met	missense	Exon 67 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152108 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00170

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00165

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00373 AC: 926 AN: 248210 AF XY: 0.00475

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.000898

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00180

Gnomad OTH exome AF: 0.00366

GnomAD4 exome AF: 0.00221 AC: 3234 AN: 1461072 Hom.: 47 Cov.: 31 AF XY: 0.00283 AC XY: 2060 AN XY: 726806

African (AFR) AF: 0.000329 AC: 11 AN: 33426

American (AMR) AF: 0.000694 AC: 31 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000843 AC: 22 AN: 26108

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39680

South Asian (SAS) AF: 0.0210 AC: 1806 AN: 86198

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53390

Middle Eastern (MID) AF: 0.00434 AC: 25 AN: 5760

European-Non Finnish (NFE) AF: 0.00105 AC: 1171 AN: 1111470

Other (OTH) AF: 0.00268 AC: 162 AN: 60340

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152226 Hom.: 5 Cov.: 33 AF XY: 0.00206 AC XY: 153 AN XY: 74422

African (AFR) AF: 0.000168 AC: 7 AN: 41564

American (AMR) AF: 0.00170 AC: 26 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.0244 AC: 118 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00165 AC: 112 AN: 67982

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.00168 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000523 AC: 2

ESP6500EA AF: 0.00193 AC: 16

ExAC AF: 0.00427 AC: 516

Asia WGS AF: 0.00924 AC: 32 AN: 3478

EpiCase AF: 0.00268

EpiControl AF: 0.00273

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	5	not provided (6)
-	-	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	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.8
DANN	Benign	0.62
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.71
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.090
Sift	Benign	0.11	T
Polyphen		0.0010	B
Vest4		0.28
MVP		0.13
MPC		0.086
ClinPred		0.011	T
GERP RS		-6.7
Mutation Taster		=94/6	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: rs146627500; hg19: chr2-179591917;