rs36043230

Variant names:

• chr2-178612540-T-G
• rs36043230
• NM_001267550.2:c.49985A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178612540-T-G
• chr2-178612540-T-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.49985A>C​(p.Asn16662Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,611,642 control chromosomes in the GnomAD database, including 478 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (29 hom., cov: 32)
  • Exomes 𝑓: 0.020 (449 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 2.69
• 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=0.0059504807).
• BP6: Variant 2-178612540-T-G is Benign according to our data. Variant chr2-178612540-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 47037.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 = 0.0143 (2180/151992) while in subpopulation NFE AF = 0.0213 (1443/67906). AF 95% confidence interval is 0.0203. There are 29 homozygotes in GnomAd4. There are 1003 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 29 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.49985A>C	p.Asn16662Thr	missense	Exon 266 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.45062A>C	p.Asn15021Thr	missense	Exon 216 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.42281A>C	p.Asn14094Thr	missense	Exon 215 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.49985A>C	p.Asn16662Thr	missense	Exon 266 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.49829A>C	p.Asn16610Thr	missense	Exon 264 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.49709A>C	p.Asn16570Thr	missense	Exon 264 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2183 AN: 151874 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00362

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.0533

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0216

GnomAD2 exomes AF: 0.0160 AC: 3888 AN: 242916 AF XY: 0.0163

Gnomad AFR exome AF: 0.00298

Gnomad AMR exome AF: 0.00924

Gnomad ASJ exome AF: 0.0548

Gnomad EAS exome AF: 0.0000569

Gnomad FIN exome AF: 0.0142

Gnomad NFE exome AF: 0.0215

Gnomad OTH exome AF: 0.0188

GnomAD4 exome AF: 0.0201 AC: 29274 AN: 1459650 Hom.: 449 Cov.: 33 AF XY: 0.0198 AC XY: 14362 AN XY: 726072

African (AFR) AF: 0.00299 AC: 100 AN: 33404

American (AMR) AF: 0.0102 AC: 457 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 1387 AN: 26104

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39414

South Asian (SAS) AF: 0.00818 AC: 705 AN: 86138

European-Finnish (FIN) AF: 0.0143 AC: 758 AN: 52876

Middle Eastern (MID) AF: 0.0330 AC: 190 AN: 5754

European-Non Finnish (NFE) AF: 0.0219 AC: 24343 AN: 1111100

Other (OTH) AF: 0.0221 AC: 1333 AN: 60256

GnomAD4 genome AF: 0.0143 AC: 2180 AN: 151992 Hom.: 29 Cov.: 32 AF XY: 0.0135 AC XY: 1003 AN XY: 74262

African (AFR) AF: 0.00361 AC: 150 AN: 41520

American (AMR) AF: 0.0110 AC: 168 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.0533 AC: 185 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5114

South Asian (SAS) AF: 0.00622 AC: 30 AN: 4822

European-Finnish (FIN) AF: 0.0140 AC: 148 AN: 10590

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1443 AN: 67906

Other (OTH) AF: 0.0213 AC: 45 AN: 2110

Alfa AF: 0.0200 Hom.: 138

Bravo AF: 0.0145

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0210 AC: 81

ESP6500AA AF: 0.00341 AC: 13

ESP6500EA AF: 0.0198 AC: 163

ExAC AF: 0.0156 AC: 1884

Asia WGS AF: 0.00202 AC: 8 AN: 3476

EpiCase AF: 0.0260

EpiControl AF: 0.0230

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	12	not specified (12)
-	-	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	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.91
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0060	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.33
Sift	Benign	0.17	T
Polyphen		0.96	P
Vest4		0.37
MPC		0.33
ClinPred		0.025	T
GERP RS		5.7
Mutation Taster		=98/2	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: rs36043230; hg19: chr2-179477267;