rs72646845

Variant names:

• chr2-178590904-G-A
• rs72646845
• NM_001267550.2:c.60821C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178590904-G-A
• chr2-178590904-G-C

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.60821C>T​(p.Pro20274Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00203 in 1,612,270 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P20274S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (41 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 5.53
• Publications: 15 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=0.008635849).
• BP6: Variant 2-178590904-G-A is Benign according to our data. Variant chr2-178590904-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47165.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0014 (213/152198) while in subpopulation SAS AF = 0.0162 (78/4822). AF 95% confidence interval is 0.0133. There are 1 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 41 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.60821C>T	p.Pro20274Leu	missense	Exon 304 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.55898C>T	p.Pro18633Leu	missense	Exon 254 of 313	NP_001243779.1
	TTN	NM_133378.4		c.53117C>T	p.Pro17706Leu	missense	Exon 253 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.60821C>T	p.Pro20274Leu	missense	Exon 304 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.60665C>T	p.Pro20222Leu	missense	Exon 302 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.60545C>T	p.Pro20182Leu	missense	Exon 302 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 211 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00369 AC: 915 AN: 247896 AF XY: 0.00448

Gnomad AFR exome AF: 0.000194

Gnomad AMR exome AF: 0.000871

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000932

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.00210 AC: 3065 AN: 1460072 Hom.: 41 Cov.: 35 AF XY: 0.00261 AC XY: 1893 AN XY: 726072

African (AFR) AF: 0.000269 AC: 9 AN: 33434

American (AMR) AF: 0.000895 AC: 40 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.0169 AC: 442 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.0169 AC: 1453 AN: 86188

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53370

Middle Eastern (MID) AF: 0.0124 AC: 71 AN: 5748

European-Non Finnish (NFE) AF: 0.000803 AC: 892 AN: 1110642

Other (OTH) AF: 0.00260 AC: 157 AN: 60310

GnomAD4 genome AF: 0.00140 AC: 213 AN: 152198 Hom.: 1 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74398

African (AFR) AF: 0.000144 AC: 6 AN: 41566

American (AMR) AF: 0.000589 AC: 9 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0136 AC: 47 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10624

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

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 67982

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00172 Hom.: 6

Bravo AF: 0.00111

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00122 AC: 10

ExAC AF: 0.00377 AC: 455

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000819

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	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)
-	-	1	Hypertrophic cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	23
DANN	Benign	0.92
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
MetaRNN	Benign	0.0086	T
MetaSVM	Uncertain	0.13	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.34
MVP		0.64
MPC		0.43
ClinPred		0.10	T
GERP RS		6.1
Mutation Taster		=87/13	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: rs72646845; hg19: chr2-179455631; COSMIC: COSV60231668; COSMIC: COSV60231668;