rs757869762

Variant names:

• chr2-178696078-G-C
• rs757869762
• NM_001267550.2:c.30994C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_001267550.2(TTN):​c.30994C>G​(p.Pro10332Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000108 in 1,550,838 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 B:1
• Conservation: PhyloP100: 1.62
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014174402).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000113 (158/1399128) while in subpopulation SAS AF = 0.00191 (151/79200). AF 95% confidence interval is 0.00166. There are 1 homozygotes in GnomAdExome4. There are 120 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.30994C>G	p.Pro10332Ala	missense	Exon 114 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.30043C>G	p.Pro10015Ala	missense	Exon 112 of 313	NP_001243779.1
	TTN	NM_133378.4		c.27262C>G	p.Pro9088Ala	missense	Exon 111 of 312	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.30994C>G	p.Pro10332Ala	missense	Exon 114 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.30994C>G	p.Pro10332Ala	missense	Exon 114 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.30718C>G	p.Pro10240Ala	missense	Exon 112 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.0000593 AC: 9 AN: 151710 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00187

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000248 AC: 39 AN: 157444 AF XY: 0.000361

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000113 AC: 158 AN: 1399128 Hom.: 1 Cov.: 31 AF XY: 0.000174 AC XY: 120 AN XY: 690064

African (AFR) AF: 0.00 AC: 0 AN: 31588

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35710

South Asian (SAS) AF: 0.00191 AC: 151 AN: 79200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078802

Other (OTH) AF: 0.000103 AC: 6 AN: 57982

GnomAD4 genome AF: 0.0000593 AC: 9 AN: 151710 Hom.: 0 Cov.: 32 AF XY: 0.0000945 AC XY: 7 AN XY: 74104

African (AFR) AF: 0.00 AC: 0 AN: 41312

American (AMR) AF: 0.00 AC: 0 AN: 15220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67846

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000187 AC: 12

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	1	-	not specified (1)
-	1	-	Primary dilated cardiomyopathy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.96
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.63	T
PhyloP100		1.6
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Polyphen		0.088	B
Vest4		0.29
MutPred		0.23		Loss of glycosylation at T10013 (P = 0.1467)
MVP		0.20
MPC		0.086
ClinPred		0.18	T
GERP RS		4.8
Mutation Taster		=81/19	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: rs757869762; hg19: chr2-179560805;