6-151544572-A-C

Variant names:

• chr6-151544572-A-C
• rs200650721
• NM_025059.4:c.444A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_025059.4(CCDC170):​c.444A>C​(p.Gln148His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000887 in 1,609,328 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (3 hom.)
• Consequence: CCDC170 NM_025059.4 missense, splice_region
• Scores: Splicing: ADA: 0.0008463
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.514
• Publications: 7 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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.030461907).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.444A>C	p.Gln148His	missense splice_region	Exon 4 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.444A>C	p.Gln148His	missense splice_region	Exon 4 of 11	ENSP00000239374.6	Q8IYT3
	CCDC170	ENST00000867015.1		c.444A>C	p.Gln148His	missense splice_region	Exon 4 of 11	ENSP00000537074.1
	CCDC170	ENST00000867016.1		c.315A>C	p.Gln105His	missense splice_region	Exon 3 of 10	ENSP00000537075.1

Frequencies

GnomAD3 genomes AF: 0.000401 AC: 61 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000809

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000435 AC: 108 AN: 248362 AF XY: 0.000467

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000873

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000888

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000938 AC: 1367 AN: 1457130 Hom.: 3 Cov.: 30 AF XY: 0.000955 AC XY: 692 AN XY: 724262

African (AFR) AF: 0.0000299 AC: 1 AN: 33424

American (AMR) AF: 0.0000896 AC: 4 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39534

South Asian (SAS) AF: 0.00 AC: 0 AN: 85960

European-Finnish (FIN) AF: 0.0000939 AC: 5 AN: 53276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00119 AC: 1321 AN: 1108324

Other (OTH) AF: 0.000598 AC: 36 AN: 60188

GnomAD4 genome AF: 0.000401 AC: 61 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74356

African (AFR) AF: 0.000145 AC: 6 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000809 AC: 55 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000804 Hom.: 0

Bravo AF: 0.000510

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000272 AC: 1

ESP6500EA AF: 0.000612 AC: 5

ExAC AF: 0.000364 AC: 44

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.51
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.035
Sift	Benign	0.099	T
Sift4G	Benign	0.084	T
Polyphen		0.066	B
Vest4		0.28
MutPred		0.077		Gain of ubiquitination at K149 (P = 0.0931)
MVP		0.081
MPC		0.12
ClinPred		0.043	T
GERP RS		1.9
Varity_R		0.054
gMVP		0.066
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00085
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.030		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: rs200650721; hg19: chr6-151865707; COSMIC: COSV105001958;