rs6929137

Variant names:

• chr6-151615542-G-A
• rs6929137
• NM_025059.4:c.1810G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_025059.4(CCDC170):​c.1810G>A​(p.Val604Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,613,434 control chromosomes in the GnomAD database, including 89,807 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.36 (10415 hom., cov: 32)
  • Exomes 𝑓: 0.33 (79392 hom.)
• Consequence: CCDC170 NM_025059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 0.969
• Publications: 96 publications found

Genes affected

CCDC170 (HGNC:21177): (coiled-coil domain containing 170) The function of this gene and its encoded protein is not known. Several genome-wide association studies have implicated the region around this gene to be involved in breast cancer and bone mineral density, but no link to this specific gene has been found. [provided by RefSeq, May 2010]

ENSG00000300966 (HGNC:):

RNU6-813P (HGNC:47776): (RNA, U6 small nuclear 813, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2158027E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025059.4. 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
	CCDC170	NM_025059.4	MANE Select	c.1810G>A	p.Val604Ile	missense	Exon 10 of 11	NP_079335.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC170	ENST00000239374.8	TSL:1 MANE Select	c.1810G>A	p.Val604Ile	missense	Exon 10 of 11	ENSP00000239374.6	Q8IYT3
	CCDC170	ENST00000867015.1		c.1789G>A	p.Val597Ile	missense	Exon 10 of 11	ENSP00000537074.1
	CCDC170	ENST00000867016.1		c.1681G>A	p.Val561Ile	missense	Exon 9 of 10	ENSP00000537075.1

Frequencies

GnomAD3 genomes AF: 0.356 AC: 54147 AN: 151926 Hom.: 10397 Cov.: 32

Gnomad AFR AF: 0.499

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.273

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.319

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.365

GnomAD2 exomes AF: 0.308 AC: 76889 AN: 249358 AF XY: 0.311

Gnomad AFR exome AF: 0.503

Gnomad AMR exome AF: 0.199

Gnomad ASJ exome AF: 0.359

Gnomad EAS exome AF: 0.321

Gnomad FIN exome AF: 0.189

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.306

GnomAD4 exome AF: 0.325 AC: 475628 AN: 1461390 Hom.: 79392 Cov.: 35 AF XY: 0.326 AC XY: 236981 AN XY: 727036

African (AFR) AF: 0.498 AC: 16678 AN: 33478

American (AMR) AF: 0.207 AC: 9259 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 9478 AN: 26120

East Asian (EAS) AF: 0.280 AC: 11118 AN: 39670

South Asian (SAS) AF: 0.333 AC: 28751 AN: 86244

European-Finnish (FIN) AF: 0.192 AC: 10270 AN: 53410

Middle Eastern (MID) AF: 0.393 AC: 2267 AN: 5766

European-Non Finnish (NFE) AF: 0.330 AC: 367112 AN: 1111604

Other (OTH) AF: 0.343 AC: 20695 AN: 60374

GnomAD4 genome AF: 0.356 AC: 54199 AN: 152044 Hom.: 10415 Cov.: 32 AF XY: 0.348 AC XY: 25889 AN XY: 74314

African (AFR) AF: 0.499 AC: 20671 AN: 41446

American (AMR) AF: 0.272 AC: 4159 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1244 AN: 3466

East Asian (EAS) AF: 0.319 AC: 1647 AN: 5168

South Asian (SAS) AF: 0.329 AC: 1583 AN: 4810

European-Finnish (FIN) AF: 0.177 AC: 1874 AN: 10570

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21880 AN: 67990

Other (OTH) AF: 0.367 AC: 776 AN: 2116

Alfa AF: 0.339 Hom.: 36861

Bravo AF: 0.370

TwinsUK AF: 0.328 AC: 1215

ALSPAC AF: 0.331 AC: 1277

ESP6500AA AF: 0.495 AC: 1842

ESP6500EA AF: 0.328 AC: 2695

ExAC AF: 0.317 AC: 38302

Asia WGS AF: 0.342 AC: 1189 AN: 3478

EpiCase AF: 0.338

EpiControl AF: 0.336

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	-	-	Estrogen resistance syndrome (2)
-	1	-	CCDC170-related condition (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.0048	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.00022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.97
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.044
Sift	Benign	0.36	T
Sift4G	Benign	0.22	T
Polyphen		0.026	B
Vest4		0.018
MPC		0.096
ClinPred		0.0057	T
GERP RS		3.4
Varity_R		0.022
gMVP		0.072
Mutation Taster		=96/4	disease causing (ClinVar)

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: rs6929137; hg19: chr6-151936677; COSMIC: COSV53337542; COSMIC: COSV53337542;