2-178549450-G-A

Variant names:

• chr2-178549450-G-A
• rs72648247
• NM_001267550.2:c.92176C>T

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.92176C>T​(p.Pro30726Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00267 in 1,607,122 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (13 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:20
• Conservation: PhyloP100: 8.15
• Publications: 18 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]

ENSG00000270277 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.008055747).
• BP6: Variant 2-178549450-G-A is Benign according to our data. Variant chr2-178549450-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47520.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00198 (302/152258) while in subpopulation SAS AF = 0.0058 (28/4824). AF 95% confidence interval is 0.00413. There are 3 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.92176C>T	p.Pro30726Ser	missense	Exon 339 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.87253C>T	p.Pro29085Ser	missense	Exon 289 of 313	NP_001243779.1
	TTN	NM_133378.4		c.84472C>T	p.Pro28158Ser	missense	Exon 288 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.92176C>T	p.Pro30726Ser	missense	Exon 339 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.92020C>T	p.Pro30674Ser	missense	Exon 337 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.91900C>T	p.Pro30634Ser	missense	Exon 337 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 152140 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00268 AC: 659 AN: 245714 AF XY: 0.00307

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.000820

Gnomad ASJ exome AF: 0.00568

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00174

Gnomad NFE exome AF: 0.00329

Gnomad OTH exome AF: 0.00202

GnomAD4 exome AF: 0.00274 AC: 3981 AN: 1454864 Hom.: 13 Cov.: 34 AF XY: 0.00278 AC XY: 2009 AN XY: 722532

African (AFR) AF: 0.000452 AC: 15 AN: 33178

American (AMR) AF: 0.000948 AC: 42 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.00443 AC: 115 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39568

South Asian (SAS) AF: 0.00524 AC: 450 AN: 85842

European-Finnish (FIN) AF: 0.00124 AC: 66 AN: 53200

Middle Eastern (MID) AF: 0.00680 AC: 39 AN: 5736

European-Non Finnish (NFE) AF: 0.00283 AC: 3129 AN: 1107068

Other (OTH) AF: 0.00208 AC: 125 AN: 60018

GnomAD4 genome AF: 0.00198 AC: 302 AN: 152258 Hom.: 3 Cov.: 33 AF XY: 0.00216 AC XY: 161 AN XY: 74442

African (AFR) AF: 0.000385 AC: 16 AN: 41552

American (AMR) AF: 0.000719 AC: 11 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4824

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00310 AC: 211 AN: 68010

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00277 Hom.: 4

Bravo AF: 0.00172

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000524 AC: 2

ESP6500EA AF: 0.00230 AC: 19

ExAC AF: 0.00245 AC: 296

Asia WGS AF: 0.00289 AC: 10 AN: 3476

EpiCase AF: 0.00295

EpiControl AF: 0.00261

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	6	not provided (6)
-	1	1	Early-onset myopathy with fatal cardiomyopathy (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	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Supraventricular tachycardia (1)
-	1	-	Tibial muscular dystrophy (1)
1	-	-	Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.91
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.0081	T
MetaSVM	Uncertain	0.36	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.46
MVP		0.46
MPC		0.47
ClinPred		0.079	T
GERP RS		5.7
Mutation Taster		=74/26	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: rs72648247; hg19: chr2-179414177;