rs72677233

Variant names:

• chr2-178618036-C-T
• rs72677233
• NM_001267550.2:c.47315G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-178618036-C-T
• chr2-178618036-C-A
• chr2-178618036-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.47315G>A​(p.Arg15772Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,612,390 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R15772R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (14 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:22
• Conservation: PhyloP100: 2.99
• Publications: 18 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005768299).
• BP6: Variant 2-178618036-C-T is Benign according to our data. Variant chr2-178618036-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47010.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00291 (443/151996) while in subpopulation AMR AF = 0.0065 (99/15238). AF 95% confidence interval is 0.00546. There are 3 homozygotes in GnomAd4. There are 207 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.47315G>A	p.Arg15772Gln	missense	Exon 253 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.42392G>A	p.Arg14131Gln	missense	Exon 203 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.39611G>A	p.Arg13204Gln	missense	Exon 202 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.47315G>A	p.Arg15772Gln	missense	Exon 253 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.47159G>A	p.Arg15720Gln	missense	Exon 251 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.47039G>A	p.Arg15680Gln	missense	Exon 251 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 443 AN: 151878 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00651

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00295

Gnomad OTH AF: 0.00910

GnomAD2 exomes AF: 0.00336 AC: 831 AN: 247508 AF XY: 0.00335

Gnomad AFR exome AF: 0.000712

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00314

Gnomad OTH exome AF: 0.00533

GnomAD4 exome AF: 0.00276 AC: 4037 AN: 1460394 Hom.: 14 Cov.: 32 AF XY: 0.00283 AC XY: 2054 AN XY: 726516

African (AFR) AF: 0.00105 AC: 35 AN: 33396

American (AMR) AF: 0.00193 AC: 86 AN: 44622

Ashkenazi Jewish (ASJ) AF: 0.0338 AC: 882 AN: 26086

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39470

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86214

European-Finnish (FIN) AF: 0.000262 AC: 14 AN: 53376

Middle Eastern (MID) AF: 0.0123 AC: 71 AN: 5754

European-Non Finnish (NFE) AF: 0.00225 AC: 2500 AN: 1111200

Other (OTH) AF: 0.00483 AC: 291 AN: 60276

GnomAD4 genome AF: 0.00291 AC: 443 AN: 151996 Hom.: 3 Cov.: 33 AF XY: 0.00279 AC XY: 207 AN XY: 74298

African (AFR) AF: 0.000337 AC: 14 AN: 41514

American (AMR) AF: 0.00650 AC: 99 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5130

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10620

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00295 AC: 200 AN: 67882

Other (OTH) AF: 0.00900 AC: 19 AN: 2110

Alfa AF: 0.00363 Hom.: 9

Bravo AF: 0.00321

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000511 AC: 2

ESP6500EA AF: 0.00482 AC: 40

ExAC AF: 0.00302 AC: 365

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	11	not specified (11)
-	-	5	not provided (5)
-	-	1	Atrial fibrillation;C0007193:Primary dilated cardiomyopathy (1)
-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	19
DANN	Benign	0.93
Eigen	Benign	-0.061
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.11
Sift	Benign	0.041	D
Polyphen		0.57	P
Vest4		0.36
MVP		0.18
MPC		0.15
ClinPred		0.016	T
GERP RS		4.8
Mutation Taster		=99/1	polymorphism

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: rs72677233; hg19: chr2-179482763; COSMIC: COSV60183129; COSMIC: COSV60183129;