rs72646850

Variant names:

• chr2-178588702-G-A
• rs72646850
• NM_001267550.2:c.63023C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-178588702-G-A
• chr2-178588702-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.63023C>T​(p.Thr21008Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,613,206 control chromosomes in the GnomAD database, including 171 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0099 (12 hom., cov: 32)
  • Exomes 𝑓: 0.013 (159 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:30
• Conservation: PhyloP100: 1.23
• Publications: 13 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=0.0029550493).
• BP6: Variant 2-178588702-G-A is Benign according to our data. Variant chr2-178588702-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47188.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 = 0.00987 (1501/152132) while in subpopulation NFE AF = 0.0155 (1055/67968). AF 95% confidence interval is 0.0147. There are 12 homozygotes in GnomAd4. There are 695 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 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.63023C>T	p.Thr21008Ile	missense	Exon 304 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.58100C>T	p.Thr19367Ile	missense	Exon 254 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.55319C>T	p.Thr18440Ile	missense	Exon 253 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.63023C>T	p.Thr21008Ile	missense	Exon 304 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.62867C>T	p.Thr20956Ile	missense	Exon 302 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.62747C>T	p.Thr20916Ile	missense	Exon 302 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1501 AN: 152014 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.00280

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00198

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0129

GnomAD2 exomes AF: 0.00924 AC: 2297 AN: 248498 AF XY: 0.00935

Gnomad AFR exome AF: 0.00181

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.0146

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00228

Gnomad NFE exome AF: 0.0141

Gnomad OTH exome AF: 0.0131

GnomAD4 exome AF: 0.0126 AC: 18449 AN: 1461074 Hom.: 159 Cov.: 33 AF XY: 0.0124 AC XY: 9025 AN XY: 726820

African (AFR) AF: 0.00158 AC: 53 AN: 33442

American (AMR) AF: 0.0110 AC: 490 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 373 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39616

South Asian (SAS) AF: 0.00106 AC: 91 AN: 86212

European-Finnish (FIN) AF: 0.00242 AC: 129 AN: 53378

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5758

European-Non Finnish (NFE) AF: 0.0148 AC: 16504 AN: 1111512

Other (OTH) AF: 0.0126 AC: 762 AN: 60346

GnomAD4 genome AF: 0.00987 AC: 1501 AN: 152132 Hom.: 12 Cov.: 32 AF XY: 0.00935 AC XY: 695 AN XY: 74368

African (AFR) AF: 0.00279 AC: 116 AN: 41544

American (AMR) AF: 0.0143 AC: 218 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.000195 AC: 1 AN: 5122

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00198 AC: 21 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0155 AC: 1055 AN: 67968

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.0130 Hom.: 51

Bravo AF: 0.0103

TwinsUK AF: 0.0146 AC: 54

ALSPAC AF: 0.0104 AC: 40

ESP6500AA AF: 0.00315 AC: 12

ESP6500EA AF: 0.0163 AC: 134

ExAC AF: 0.00937 AC: 1132

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.0156

EpiControl AF: 0.0160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	5	not provided (5)
-	-	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;C0018802:Congestive heart failure;C0878544:Cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.41
DANN	Benign	0.71
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.17
Sift	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.055
MPC		0.090
ClinPred		0.0026	T
GERP RS		-6.5
Mutation Taster		=97/3	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: rs72646850; hg19: chr2-179453429; COSMIC: COSV106496798; COSMIC: COSV106496798;