rs72646869

Variant names:

• chr2-178581654-C-T
• rs72646869
• NM_001267550.2:c.66614G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178581654-C-T
• chr2-178581654-C-G

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.66614G>A​(p.Arg22205Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0179 in 1,612,710 control chromosomes in the GnomAD database, including 318 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 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. R22205R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (18 hom., cov: 32)
  • Exomes 𝑓: 0.018 (300 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 1.75
• Publications: 12 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=0.0071591735).
• BP6: Variant 2-178581654-C-T is Benign according to our data. Variant chr2-178581654-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47236.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 = 0.0126 (1923/152104) while in subpopulation NFE AF = 0.0206 (1402/67948). AF 95% confidence interval is 0.0197. There are 18 homozygotes in GnomAd4. There are 891 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 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.66614G>A	p.Arg22205Lys	missense	Exon 316 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.61691G>A	p.Arg20564Lys	missense	Exon 266 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.58910G>A	p.Arg19637Lys	missense	Exon 265 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.66614G>A	p.Arg22205Lys	missense	Exon 316 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.66458G>A	p.Arg22153Lys	missense	Exon 314 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.66338G>A	p.Arg22113Lys	missense	Exon 314 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0126 AC: 1922 AN: 151986 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00807

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0134

GnomAD2 exomes AF: 0.0137 AC: 3396 AN: 247930 AF XY: 0.0138

Gnomad AFR exome AF: 0.00349

Gnomad AMR exome AF: 0.00852

Gnomad ASJ exome AF: 0.00378

Gnomad EAS exome AF: 0.0000564

Gnomad FIN exome AF: 0.0181

Gnomad NFE exome AF: 0.0221

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0184 AC: 26881 AN: 1460606 Hom.: 300 Cov.: 32 AF XY: 0.0180 AC XY: 13058 AN XY: 726572

African (AFR) AF: 0.00338 AC: 113 AN: 33420

American (AMR) AF: 0.00846 AC: 378 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.00306 AC: 80 AN: 26104

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39474

South Asian (SAS) AF: 0.00159 AC: 137 AN: 86216

European-Finnish (FIN) AF: 0.0188 AC: 1001 AN: 53366

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5758

European-Non Finnish (NFE) AF: 0.0218 AC: 24278 AN: 1111304

Other (OTH) AF: 0.0145 AC: 872 AN: 60302

GnomAD4 genome AF: 0.0126 AC: 1923 AN: 152104 Hom.: 18 Cov.: 32 AF XY: 0.0120 AC XY: 891 AN XY: 74344

African (AFR) AF: 0.00378 AC: 157 AN: 41536

American (AMR) AF: 0.00806 AC: 123 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5146

South Asian (SAS) AF: 0.00146 AC: 7 AN: 4810

European-Finnish (FIN) AF: 0.0179 AC: 190 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0206 AC: 1402 AN: 67948

Other (OTH) AF: 0.0133 AC: 28 AN: 2108

Alfa AF: 0.0175 Hom.: 58

Bravo AF: 0.0116

TwinsUK AF: 0.0251 AC: 93

ALSPAC AF: 0.0304 AC: 117

ESP6500AA AF: 0.00427 AC: 17

ESP6500EA AF: 0.0219 AC: 182

ExAC AF: 0.0146 AC: 1771

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0183

EpiControl AF: 0.0191

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	4	not provided (4)
-	-	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	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.92
Eigen	Benign	-0.081
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.045	N
PhyloP100		1.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.069
Sift	Benign	0.57	T
Polyphen		0.021	B
Vest4		0.33
MPC		0.091
ClinPred		0.016	T
GERP RS		5.4
Mutation Taster		=97/3	polymorphism (auto)

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: rs72646869; hg19: chr2-179446381; COSMIC: COSV107416119; COSMIC: COSV107416119;