rs72650031

Variant names:

• chr2-178684680-G-A
• rs72650031
• NM_001267550.2:c.32624C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178684680-G-A
• chr2-178684680-G-C
• chr2-178684680-G-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.32624C>T​(p.Pro10875Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00606 in 1,609,214 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (51 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:23
• Conservation: PhyloP100: 1.50
• Publications: 16 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]

LOC124906100 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047104955).
• BP6: Variant 2-178684680-G-A is Benign according to our data. Variant chr2-178684680-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46873.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00442 (672/152134) while in subpopulation NFE AF = 0.00611 (415/67952). AF 95% confidence interval is 0.00562. There are 4 homozygotes in GnomAd4. There are 318 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.32624C>T	p.Pro10875Leu	missense	Exon 131 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31673C>T	p.Pro10558Leu	missense	Exon 129 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.28892C>T	p.Pro9631Leu	missense	Exon 128 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.32624C>T	p.Pro10875Leu	missense	Exon 131 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32624C>T	p.Pro10875Leu	missense	Exon 131 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32348C>T	p.Pro10783Leu	missense	Exon 129 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00442 AC: 672 AN: 152018 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00512

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00611

Gnomad OTH AF: 0.00672

GnomAD2 exomes AF: 0.00544 AC: 1329 AN: 244514 AF XY: 0.00542

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00503

Gnomad ASJ exome AF: 0.0315

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000793

Gnomad NFE exome AF: 0.00650

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00623 AC: 9080 AN: 1457080 Hom.: 51 Cov.: 32 AF XY: 0.00624 AC XY: 4519 AN XY: 724646

African (AFR) AF: 0.00109 AC: 36 AN: 32936

American (AMR) AF: 0.00484 AC: 212 AN: 43820

Ashkenazi Jewish (ASJ) AF: 0.0298 AC: 773 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00189 AC: 160 AN: 84806

European-Finnish (FIN) AF: 0.000769 AC: 41 AN: 53344

Middle Eastern (MID) AF: 0.0138 AC: 79 AN: 5726

European-Non Finnish (NFE) AF: 0.00658 AC: 7307 AN: 1110682

Other (OTH) AF: 0.00785 AC: 472 AN: 60136

GnomAD4 genome AF: 0.00442 AC: 672 AN: 152134 Hom.: 4 Cov.: 32 AF XY: 0.00427 AC XY: 318 AN XY: 74396

African (AFR) AF: 0.00130 AC: 54 AN: 41530

American (AMR) AF: 0.00511 AC: 78 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4822

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10602

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00611 AC: 415 AN: 67952

Other (OTH) AF: 0.00665 AC: 14 AN: 2106

Alfa AF: 0.00652 Hom.: 19

Bravo AF: 0.00465

TwinsUK AF: 0.00890 AC: 33

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000818 AC: 3

ESP6500EA AF: 0.00588 AC: 48

ExAC AF: 0.00504 AC: 609

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00927

EpiControl AF: 0.00937

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	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	Limb-girdle muscular dystrophy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Supraventricular tachycardia;C0042514:Ventricular tachycardia;C1142166:Brugada syndrome (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Benign	0.83
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.0064
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.89	T
PhyloP100		1.5
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.099
Sift	Uncertain	0.018	D
Polyphen		0.0010	B
Vest4		0.31
MVP		0.40
MPC		0.085
ClinPred		0.015	T
GERP RS		4.8
Mutation Taster		=35/65	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: rs72650031; hg19: chr2-179549407; COSMIC: COSV59952896;