rs72677225

Variant names:

• chr2-178621310-C-A
• rs72677225
• NM_001267550.2:c.45408G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178621310-C-A
• chr2-178621310-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.45408G>T​(p.Lys15136Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00666 in 1,611,922 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0050 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0068 (41 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:23
• Conservation: PhyloP100: 1.28
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008456409).
• BP6: Variant 2-178621310-C-A is Benign according to our data. Variant chr2-178621310-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46988.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00501 (762/151988) while in subpopulation NFE AF = 0.00845 (574/67890). AF 95% confidence interval is 0.00788. There are 3 homozygotes in GnomAd4. There are 350 alleles in the male GnomAd4 subpopulation. Median coverage is 32. 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.45408G>T	p.Lys15136Asn	missense	Exon 246 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.40485G>T	p.Lys13495Asn	missense	Exon 196 of 313	NP_001243779.1
	TTN	NM_133378.4		c.37704G>T	p.Lys12568Asn	missense	Exon 195 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.45408G>T	p.Lys15136Asn	missense	Exon 246 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.45252G>T	p.Lys15084Asn	missense	Exon 244 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.45132G>T	p.Lys15044Asn	missense	Exon 244 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 761 AN: 151870 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00158

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00698

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00844

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00511 AC: 1260 AN: 246454 AF XY: 0.00515

Gnomad AFR exome AF: 0.00149

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00300

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00836

Gnomad NFE exome AF: 0.00779

Gnomad OTH exome AF: 0.00588

GnomAD4 exome AF: 0.00683 AC: 9972 AN: 1459934 Hom.: 41 Cov.: 32 AF XY: 0.00673 AC XY: 4887 AN XY: 726236

African (AFR) AF: 0.000989 AC: 33 AN: 33380

American (AMR) AF: 0.00227 AC: 101 AN: 44538

Ashkenazi Jewish (ASJ) AF: 0.00253 AC: 66 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39424

South Asian (SAS) AF: 0.00175 AC: 151 AN: 86126

European-Finnish (FIN) AF: 0.00683 AC: 364 AN: 53286

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5754

European-Non Finnish (NFE) AF: 0.00801 AC: 8897 AN: 1111098

Other (OTH) AF: 0.00568 AC: 342 AN: 60242

GnomAD4 genome AF: 0.00501 AC: 762 AN: 151988 Hom.: 3 Cov.: 32 AF XY: 0.00471 AC XY: 350 AN XY: 74272

African (AFR) AF: 0.00135 AC: 56 AN: 41526

American (AMR) AF: 0.00157 AC: 24 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.00231 AC: 8 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00698 AC: 74 AN: 10606

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00845 AC: 574 AN: 67890

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.00674 Hom.: 11

Bravo AF: 0.00427

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.000548 AC: 2

ESP6500EA AF: 0.00859 AC: 70

ExAC AF: 0.00457 AC: 551

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00715

EpiControl AF: 0.00708

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	1	4	not provided (5)
-	-	2	Cardiomyopathy (2)
-	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	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)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.97
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.18
Sift	Uncertain	0.025	D
Polyphen		0.98	D
Vest4		0.49
MutPred		0.39		Loss of ubiquitination at K13495 (P = 0.0161)
MVP		0.18
MPC		0.38
ClinPred		0.029	T
GERP RS		3.4
Mutation Taster		=99/1	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: rs72677225; hg19: chr2-179486037;