rs149748934

Variant names:

• chr2-178748452-G-A
• rs149748934
• NM_001267550.2:c.11311+4672C>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_133379.5(TTN):​c.13948C>T​(p.Pro4650Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00339 in 1,612,962 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P4650R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: TTN NM_133379.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -1.06
• Publications: 10 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=0.0030308366).
• BP6: Variant 2-178748452-G-A is Benign according to our data. Variant chr2-178748452-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00233 (354/151998) while in subpopulation NFE AF = 0.0038 (258/67898). AF 95% confidence interval is 0.00342. There are 0 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 11 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133379.5. 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.11311+4672C>T		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_133379.5		c.13948C>T	p.Pro4650Ser	missense	Exon 46 of 46	NP_596870.2	Q8WZ42-6
	TTN	NM_001256850.1		c.10360+4672C>T		intron	N/A	NP_001243779.1	Q8WZ42-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.11311+4672C>T		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.11311+4672C>T		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.11035+4672C>T		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 151880 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00178

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00380

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00198 AC: 493 AN: 248742 AF XY: 0.00195

Gnomad AFR exome AF: 0.000754

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00160

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00350 AC: 5113 AN: 1460964 Hom.: 11 Cov.: 35 AF XY: 0.00339 AC XY: 2461 AN XY: 726798

African (AFR) AF: 0.000568 AC: 19 AN: 33438

American (AMR) AF: 0.00121 AC: 54 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00199 AC: 52 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86238

European-Finnish (FIN) AF: 0.000712 AC: 38 AN: 53350

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5760

European-Non Finnish (NFE) AF: 0.00431 AC: 4787 AN: 1111434

Other (OTH) AF: 0.00237 AC: 143 AN: 60330

GnomAD4 genome AF: 0.00233 AC: 354 AN: 151998 Hom.: 0 Cov.: 32 AF XY: 0.00222 AC XY: 165 AN XY: 74308

African (AFR) AF: 0.000747 AC: 31 AN: 41502

American (AMR) AF: 0.00177 AC: 27 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10604

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

European-Non Finnish (NFE) AF: 0.00380 AC: 258 AN: 67898

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00305 Hom.: 3

Bravo AF: 0.00250

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00194 AC: 236

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not provided (8)
-	-	4	not specified (4)
-	-	1	Limb-girdle muscular dystrophy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	0.44
DANN	Benign	0.34
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.1
PROVEAN	Benign	0.74	N
REVEL	Benign	0.017
Sift	Pathogenic	0.0	D
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.067
MVP		0.040
ClinPred		0.0035	T
GERP RS		-4.2
Mutation Taster		=100/0	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: rs149748934; hg19: chr2-179613179;