rs57389274

Variant names:

• chr2-178756626-G-A
• rs57389274
• NM_001267550.2:c.10850C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.10850C>T​(p.Ser3617Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 1,613,678 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (79 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (67 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 2.86
• Publications: 7 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=0.0024047792).
• BP6: Variant 2-178756626-G-A is Benign according to our data. Variant chr2-178756626-G-A is described in ClinVar as Benign. ClinVar VariationId is 47847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0566 is higher than 0.05.

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.10850C>T	p.Ser3617Phe	missense	Exon 46 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_133437.4		c.10337C>T	p.Ser3446Phe	missense	Exon 44 of 192	NP_597681.4	A0A0A0MRA3
	TTN	NM_001256850.1		c.10303+2358C>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.10850C>T	p.Ser3617Phe	missense	Exon 46 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10850C>T	p.Ser3617Phe	missense	Exon 46 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.10574C>T	p.Ser3525Phe	missense	Exon 44 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2519 AN: 152112 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.0583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00395 AC: 981 AN: 248612 AF XY: 0.00300

Gnomad AFR exome AF: 0.0563

Gnomad AMR exome AF: 0.00220

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000151

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.00169 AC: 2475 AN: 1461448 Hom.: 67 Cov.: 33 AF XY: 0.00143 AC XY: 1038 AN XY: 727004

African (AFR) AF: 0.0617 AC: 2065 AN: 33462

American (AMR) AF: 0.00253 AC: 113 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5766

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1111738

Other (OTH) AF: 0.00379 AC: 229 AN: 60366

GnomAD4 genome AF: 0.0167 AC: 2538 AN: 152230 Hom.: 79 Cov.: 32 AF XY: 0.0159 AC XY: 1181 AN XY: 74418

African (AFR) AF: 0.0585 AC: 2432 AN: 41538

American (AMR) AF: 0.00386 AC: 59 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 68010

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00552 Hom.: 84

Bravo AF: 0.0193

ESP6500AA AF: 0.0498 AC: 191

ESP6500EA AF: 0.000726 AC: 6

ExAC AF: 0.00516 AC: 623

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.94
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.9
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.039
Sift	Benign	0.053	T
Vest4		0.19
MVP		0.62
MPC		0.10
ClinPred		0.013	T
GERP RS		3.3
Mutation Taster		=94/6	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: rs57389274; hg19: chr2-179621353;