rs2291310

Variant names:

• chr2-178759031-C-T
• rs2291310
• NM_001267550.2:c.10256G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178759031-C-T
• chr2-178759031-C-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.10256G>A​(p.Ser3419Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.901 in 1,613,868 control chromosomes in the GnomAD database, including 659,693 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 Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S3419I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.87 (58493 hom., cov: 32)
  • Exomes 𝑓: 0.90 (601200 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:25
• Conservation: PhyloP100: 0.424
• Publications: 42 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=1.0760812E-6).
• BP6: Variant 2-178759031-C-T is Benign according to our data. Variant chr2-178759031-C-T is described in ClinVar as Benign. ClinVar VariationId is 46582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 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.10256G>A	p.Ser3419Asn	missense	Exon 44 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.10256G>A	p.Ser3419Asn	missense	Exon 44 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.10256G>A	p.Ser3419Asn	missense	Exon 44 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.10256G>A	p.Ser3419Asn	missense	Exon 44 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.10256G>A	p.Ser3419Asn	missense	Exon 44 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.9980G>A	p.Ser3327Asn	missense	Exon 42 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132817 AN: 152050 Hom.: 58459 Cov.: 32

Gnomad AFR AF: 0.845

Gnomad AMI AF: 0.952

Gnomad AMR AF: 0.720

Gnomad ASJ AF: 0.918

Gnomad EAS AF: 0.791

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.892

Gnomad MID AF: 0.949

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.898

GnomAD2 exomes AF: 0.841 AC: 211211 AN: 251152 AF XY: 0.852

Gnomad AFR exome AF: 0.847

Gnomad AMR exome AF: 0.571

Gnomad ASJ exome AF: 0.913

Gnomad EAS exome AF: 0.768

Gnomad FIN exome AF: 0.892

Gnomad NFE exome AF: 0.930

Gnomad OTH exome AF: 0.871

GnomAD4 exome AF: 0.904 AC: 1321141 AN: 1461700 Hom.: 601200 Cov.: 63 AF XY: 0.903 AC XY: 656319 AN XY: 727154

African (AFR) AF: 0.846 AC: 28322 AN: 33478

American (AMR) AF: 0.586 AC: 26205 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.917 AC: 23956 AN: 26130

East Asian (EAS) AF: 0.792 AC: 31403 AN: 39670

South Asian (SAS) AF: 0.796 AC: 68672 AN: 86254

European-Finnish (FIN) AF: 0.889 AC: 47482 AN: 53414

Middle Eastern (MID) AF: 0.929 AC: 5356 AN: 5764

European-Non Finnish (NFE) AF: 0.931 AC: 1035540 AN: 1111884

Other (OTH) AF: 0.898 AC: 54205 AN: 60386

GnomAD4 genome AF: 0.873 AC: 132893 AN: 152168 Hom.: 58493 Cov.: 32 AF XY: 0.868 AC XY: 64528 AN XY: 74370

African (AFR) AF: 0.844 AC: 35045 AN: 41506

American (AMR) AF: 0.719 AC: 10979 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 3187 AN: 3470

East Asian (EAS) AF: 0.790 AC: 4085 AN: 5170

South Asian (SAS) AF: 0.790 AC: 3810 AN: 4820

European-Finnish (FIN) AF: 0.892 AC: 9449 AN: 10596

Middle Eastern (MID) AF: 0.949 AC: 279 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63291 AN: 68012

Other (OTH) AF: 0.900 AC: 1900 AN: 2112

Alfa AF: 0.910 Hom.: 280873

Bravo AF: 0.857

TwinsUK AF: 0.931 AC: 3453

ALSPAC AF: 0.929 AC: 3581

ESP6500AA AF: 0.844 AC: 3717

ESP6500EA AF: 0.932 AC: 8019

ExAC AF: 0.851 AC: 103320

Asia WGS AF: 0.801 AC: 2790 AN: 3478

EpiCase AF: 0.935

EpiControl AF: 0.932

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	14
DANN	Benign	0.78
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0000011	T
MetaSVM	Benign	-0.98	T
PhyloP100		0.42
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.10
Sift	Benign	0.63	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.053
MPC		0.078
ClinPred		0.0026	T
GERP RS		-3.2
Mutation Taster		=64/36	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: rs2291310; hg19: chr2-179623758; COSMIC: COSV107410185;