NM_001267550.2:c.38929C>T

Variant names:

• chr2-178652878-G-A
• rs150223722
• NM_001267550.2:c.38929C>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.38929C>T​(p.Pro12977Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,611,716 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P12977P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0039 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0064 (61 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.120
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00516212).
• BP6: Variant 2-178652878-G-A is Benign according to our data. Variant chr2-178652878-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 238766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00395 (601/152160) while in subpopulation SAS AF = 0.0207 (100/4820). AF 95% confidence interval is 0.0175. There are 5 homozygotes in GnomAd4. There are 290 alleles in the male GnomAd4 subpopulation. Median coverage is 31. 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.38929C>T	p.Pro12977Ser	missense	Exon 200 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34523-337C>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31742-337C>T		intron	N/A	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.38929C>T	p.Pro12977Ser	missense	Exon 200 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.38929C>T	p.Pro12977Ser	missense	Exon 200 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.38653C>T	p.Pro12885Ser	missense	Exon 198 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00393 AC: 598 AN: 152042 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.00170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00577

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00597 AC: 1457 AN: 244164 AF XY: 0.00701

Gnomad AFR exome AF: 0.000956

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.000112

Gnomad FIN exome AF: 0.00121

Gnomad NFE exome AF: 0.00577

Gnomad OTH exome AF: 0.00594

GnomAD4 exome AF: 0.00639 AC: 9324 AN: 1459556 Hom.: 61 Cov.: 34 AF XY: 0.00691 AC XY: 5020 AN XY: 726064

African (AFR) AF: 0.000962 AC: 32 AN: 33248

American (AMR) AF: 0.00198 AC: 88 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.000231 AC: 6 AN: 26012

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39658

South Asian (SAS) AF: 0.0232 AC: 1993 AN: 85902

European-Finnish (FIN) AF: 0.00131 AC: 70 AN: 53278

Middle Eastern (MID) AF: 0.0106 AC: 61 AN: 5728

European-Non Finnish (NFE) AF: 0.00606 AC: 6732 AN: 1111148

Other (OTH) AF: 0.00565 AC: 340 AN: 60214

GnomAD4 genome AF: 0.00395 AC: 601 AN: 152160 Hom.: 5 Cov.: 31 AF XY: 0.00390 AC XY: 290 AN XY: 74376

African (AFR) AF: 0.00104 AC: 43 AN: 41544

American (AMR) AF: 0.00236 AC: 36 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.0207 AC: 100 AN: 4820

European-Finnish (FIN) AF: 0.00170 AC: 18 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00577 AC: 392 AN: 67978

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000748 Hom.: 0

Bravo AF: 0.00327

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000571 AC: 1

ESP6500EA AF: 0.00678 AC: 27

ExAC AF: 0.00636 AC: 765

Asia WGS AF: 0.0120 AC: 40 AN: 3478

EpiCase AF: 0.00639

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (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	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.57
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.73	T
MetaRNN	Benign	0.0052	T
PhyloP100		0.12
Vest4		0.17
MVP		0.84
GERP RS		3.9
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs150223722; hg19: chr2-179517605;