rs72646873

Variant names:

• chr2-178580188-A-G
• rs72646873
• NM_001267550.2:c.67099T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178580188-A-G
• chr2-178580188-A-T

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.67099T>C​(p.Ser22367Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0033 in 1,613,164 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (14 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:4 B:20
• Conservation: PhyloP100: 2.90
• Publications: 12 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]

ENSG00000270574 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009555876).
• BP6: Variant 2-178580188-A-G is Benign according to our data. Variant chr2-178580188-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 47248.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00188 (286/152228) while in subpopulation AMR AF = 0.00288 (44/15278). AF 95% confidence interval is 0.00232. There are 0 homozygotes in GnomAd4. There are 137 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 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.67099T>C	p.Ser22367Pro	missense	Exon 318 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.62176T>C	p.Ser20726Pro	missense	Exon 268 of 313	NP_001243779.1
	TTN	NM_133378.4		c.59395T>C	p.Ser19799Pro	missense	Exon 267 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.67099T>C	p.Ser22367Pro	missense	Exon 318 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.66943T>C	p.Ser22315Pro	missense	Exon 316 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.66823T>C	p.Ser22275Pro	missense	Exon 316 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152110 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00263

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00174 AC: 431 AN: 247956 AF XY: 0.00194

Gnomad AFR exome AF: 0.000452

Gnomad AMR exome AF: 0.000871

Gnomad ASJ exome AF: 0.00329

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00248

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.00345 AC: 5033 AN: 1460936 Hom.: 14 Cov.: 36 AF XY: 0.00343 AC XY: 2495 AN XY: 726732

African (AFR) AF: 0.000538 AC: 18 AN: 33436

American (AMR) AF: 0.00101 AC: 45 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00337 AC: 88 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39566

South Asian (SAS) AF: 0.00211 AC: 182 AN: 86214

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53364

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5754

European-Non Finnish (NFE) AF: 0.00404 AC: 4495 AN: 1111482

Other (OTH) AF: 0.00320 AC: 193 AN: 60318

GnomAD4 genome AF: 0.00188 AC: 286 AN: 152228 Hom.: 0 Cov.: 33 AF XY: 0.00184 AC XY: 137 AN XY: 74414

African (AFR) AF: 0.000746 AC: 31 AN: 41576

American (AMR) AF: 0.00288 AC: 44 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

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

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00263 AC: 179 AN: 67990

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00239 Hom.: 0

Bravo AF: 0.00221

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000269 AC: 1

ESP6500EA AF: 0.00183 AC: 15

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	4	not provided (5)
-	1	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiomyopathy;C1142166:Brugada syndrome (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	-	-	Tip-toe gait (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.94
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0096	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.9
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.016	D
Polyphen		0.95	P
Vest4		0.39
MVP		0.23
MPC		0.31
ClinPred		0.057	T
GERP RS		4.5
Mutation Taster		=56/44	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: rs72646873; hg19: chr2-179444915;