rs75686037

Variant names:

• chr2-178776633-G-A
• rs75686037
• NM_001267550.2:c.5231C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.5231C>T​(p.Pro1744Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,036 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (40 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 9.83
• Publications: 19 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009172559).
• BP6: Variant 2-178776633-G-A is Benign according to our data. Variant chr2-178776633-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0024 (365/152276) while in subpopulation EAS AF = 0.027 (140/5180). AF 95% confidence interval is 0.0234. There are 8 homozygotes in GnomAd4. There are 177 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.5231C>T	p.Pro1744Leu	missense	Exon 28 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.5231C>T	p.Pro1744Leu	missense	Exon 28 of 313	NP_001243779.1
	TTN	NM_133378.4		c.5231C>T	p.Pro1744Leu	missense	Exon 28 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.5231C>T	p.Pro1744Leu	missense	Exon 28 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.5231C>T	p.Pro1744Leu	missense	Exon 28 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.4955C>T	p.Pro1652Leu	missense	Exon 26 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 362 AN: 152158 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0122

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0268

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00726 AC: 1820 AN: 250768 AF XY: 0.00565

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0362

Gnomad ASJ exome AF: 0.000596

Gnomad EAS exome AF: 0.0260

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000291

Gnomad OTH exome AF: 0.00442

GnomAD4 exome AF: 0.00195 AC: 2847 AN: 1461760 Hom.: 40 Cov.: 33 AF XY: 0.00174 AC XY: 1265 AN XY: 727184

African (AFR) AF: 0.000388 AC: 13 AN: 33474

American (AMR) AF: 0.0334 AC: 1493 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.000765 AC: 20 AN: 26134

East Asian (EAS) AF: 0.0229 AC: 908 AN: 39662

South Asian (SAS) AF: 0.000835 AC: 72 AN: 86258

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53392

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000194 AC: 216 AN: 1111980

Other (OTH) AF: 0.00187 AC: 113 AN: 60392

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152276 Hom.: 8 Cov.: 32 AF XY: 0.00238 AC XY: 177 AN XY: 74446

African (AFR) AF: 0.000241 AC: 10 AN: 41542

American (AMR) AF: 0.0123 AC: 188 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0270 AC: 140 AN: 5180

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68020

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00173 Hom.: 13

Bravo AF: 0.00462

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00638 AC: 775

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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	not provided (1)
-	-	1	Ventricular tachycardia;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-0.29	T
PhyloP100		9.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-6.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.44
MVP		0.76
MPC		0.47
ClinPred		0.067	T
GERP RS		5.0
Mutation Taster		=69/31	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: rs75686037; hg19: chr2-179641360;