rs4893853

Variant names:

• chr2-178767769-T-C
• rs4893853
• NM_001267550.2:c.9461A>G

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.9461A>G​(p.Lys3154Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.04 in 1,614,038 control chromosomes in the GnomAD database, including 3,038 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 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. K3154K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.054 (365 hom., cov: 32)
  • Exomes 𝑓: 0.039 (2673 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24
• Conservation: PhyloP100: 1.86
• Publications: 17 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=0.0013342202).
• BP6: Variant 2-178767769-T-C is Benign according to our data. Variant chr2-178767769-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47648.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.152 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.9461A>G	p.Lys3154Arg	missense	Exon 40 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.9461A>G	p.Lys3154Arg	missense	Exon 40 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.9461A>G	p.Lys3154Arg	missense	Exon 40 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.9461A>G	p.Lys3154Arg	missense	Exon 40 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.9461A>G	p.Lys3154Arg	missense	Exon 40 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9185A>G	p.Lys3062Arg	missense	Exon 38 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0535 AC: 8147 AN: 152196 Hom.: 358 Cov.: 32

Gnomad AFR AF: 0.0701

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.135

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.0217

Gnomad SAS AF: 0.162

Gnomad FIN AF: 0.0570

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.0378

GnomAD2 exomes AF: 0.0704 AC: 17666 AN: 250894 AF XY: 0.0692

Gnomad AFR exome AF: 0.0710

Gnomad AMR exome AF: 0.186

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.0252

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0555

GnomAD4 exome AF: 0.0386 AC: 56358 AN: 1461724 Hom.: 2673 Cov.: 30 AF XY: 0.0413 AC XY: 29996 AN XY: 727168

African (AFR) AF: 0.0687 AC: 2299 AN: 33478

American (AMR) AF: 0.182 AC: 8148 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0280 AC: 732 AN: 26134

East Asian (EAS) AF: 0.0124 AC: 493 AN: 39694

South Asian (SAS) AF: 0.162 AC: 13931 AN: 86256

European-Finnish (FIN) AF: 0.0563 AC: 3003 AN: 53320

Middle Eastern (MID) AF: 0.0470 AC: 271 AN: 5766

European-Non Finnish (NFE) AF: 0.0224 AC: 24896 AN: 1111966

Other (OTH) AF: 0.0428 AC: 2585 AN: 60390

GnomAD4 genome AF: 0.0536 AC: 8161 AN: 152314 Hom.: 365 Cov.: 32 AF XY: 0.0585 AC XY: 4356 AN XY: 74472

African (AFR) AF: 0.0700 AC: 2911 AN: 41578

American (AMR) AF: 0.135 AC: 2071 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3472

East Asian (EAS) AF: 0.0220 AC: 114 AN: 5190

South Asian (SAS) AF: 0.161 AC: 778 AN: 4824

European-Finnish (FIN) AF: 0.0570 AC: 605 AN: 10612

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0221 AC: 1505 AN: 68022

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0308 Hom.: 572

Bravo AF: 0.0564

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0195 AC: 75

ESP6500AA AF: 0.0719 AC: 317

ESP6500EA AF: 0.0212 AC: 182

ExAC AF: 0.0657 AC: 7981

Asia WGS AF: 0.106 AC: 367 AN: 3478

EpiCase AF: 0.0210

EpiControl AF: 0.0216

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Benign	0.96
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-1.0	T
PhyloP100		1.9
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.064
Sift	Benign	0.44	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.095
MPC		0.070
ClinPred		0.0017	T
GERP RS		2.1
PromoterAI		-0.0052	Neutral
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4893853; hg19: chr2-179632496; COSMIC: COSV60092748; COSMIC: COSV60092748;